WO2022076622A2 - Modulateurs du régulateur de la conductance transmembranaire de la fibrose kystique - Google Patents

Modulateurs du régulateur de la conductance transmembranaire de la fibrose kystique Download PDF

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WO2022076622A2
WO2022076622A2 PCT/US2021/053858 US2021053858W WO2022076622A2 WO 2022076622 A2 WO2022076622 A2 WO 2022076622A2 US 2021053858 W US2021053858 W US 2021053858W WO 2022076622 A2 WO2022076622 A2 WO 2022076622A2
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independently selected
optionally substituted
groups independently
alkyl
alkoxy
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PCT/US2021/053858
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WO2022076622A3 (fr
Inventor
Jason Mccartney
Alexander Russell Abela
Sunny Abraham
Corey Don Anderson
Vijayalaksmi Arumugam
Jaclyn CHAU
Jeremy Clemens
Thomas Cleveland
Timothy Richard Coon
Timothy A. DWIGHT
Lev Tyler Dewey Fanning
Bryan A. Frieman
Anton V. Gulevich
Sara Sabina Hadida Ruah
Yoshihiro Ishihara
Haripada Khatuya
Paul Krenitsky
Vito Melillo
Mark Thomas Miller
Prasuna PARASELLI
Fabrice Pierre
Alina Silina
Joe A. Tran
Johnny Uy
Lino Valdez
Troy Vickers
Jinglan Zhou
Peter Grootenhuis
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Vertex Pharmaceuticals Incorporated
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Priority to MX2023004072A priority Critical patent/MX2023004072A/es
Priority to JP2023521520A priority patent/JP2023545080A/ja
Priority to IL301757A priority patent/IL301757A/en
Priority to CR20230198A priority patent/CR20230198A/es
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to CN202180082021.0A priority patent/CN116601158A/zh
Priority to EP21830544.9A priority patent/EP4225765A2/fr
Priority to KR1020237015292A priority patent/KR20230107725A/ko
Priority to CA3197683A priority patent/CA3197683A1/fr
Priority to AU2021358512A priority patent/AU2021358512A1/en
Priority to US18/248,071 priority patent/US20240150377A1/en
Priority to PE2023001370A priority patent/PE20231108A1/es
Publication of WO2022076622A2 publication Critical patent/WO2022076622A2/fr
Publication of WO2022076622A3 publication Critical patent/WO2022076622A3/fr
Priority to DO2023000067A priority patent/DOP2023000067A/es
Priority to CONC2023/0005006A priority patent/CO2023005006A2/es

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D515/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Cystic fibrosis is a recessive genetic disease that affects approximately 70,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure.
  • CFTR mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients.
  • CF patients In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death.
  • the CFTR2 database contains information on only 432 of these identified mutations, with sufficient evidence to define 352 mutations as disease causing.
  • the most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as the F508del mutation. This mutation occurs in many of the cases of cystic fibrosis and is associated with severe disease. [0006]
  • the deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the endoplasmic reticulum (ER) and traffic to the plasma membrane.
  • ER endoplasmic reticulum
  • the number of CFTR channels for anion transport present in the membrane is far less than observed in cells expressing wild-type CFTR, i.e., CFTR having no mutations.
  • the mutation results in defective channel gating.
  • the reduced number of channels in the membrane and the defective gating lead to reduced anion and fluid transport across epithelia.
  • the channels that are defective because of the F508del mutation are still functional, albeit less functional than wild-type CFTR channels.
  • CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue.
  • CFTR is composed of 1480 amino acids that encode a protein which is made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
  • R regulatory
  • Chloride transport takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na + -K + -ATPase pump and Cl- channels expressed on the basolateral surface of the cell.
  • One aspect of the disclosure provides novel compounds, including compounds of Formula I, compounds of any of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • Formula I encompasses compounds falling within the following structure: and includes tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; Ring B is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; V is selected from O and NH; W 1 is selected from N and CH; W 2 is selected from N and CH, provided that at least one of W 1 and W 2 is N; Z is selected from O, NR ZN , and C(R ZC ) 2 , provided that when L 2 is absent, Z is C(R ZC ) 2
  • Formula I encompasses compounds of Formula Ia falling within the following structure: and includes tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; Ring B is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; V is selected from O and NH; W 1 is selected from N and CH; W 2 is selected from N and CH, provided that at least one of W 1 and W 2 is N; Z is selected from O, NR ZN , and C(R ZC ) 2 , provided that when L 2 is absent, Z is C(R Z
  • Formula I also includes compounds of Formula Ib: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula Ia.
  • Formula I also includes compounds of Formula IIa: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula Ia.
  • Formula I also includes compounds of Formula IIb: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula la.
  • Formula I also includes compounds of Formula III: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula la.
  • Formula I also includes compounds of Formula IV: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula la.
  • Formula I also includes compounds of Formula V: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula la.
  • Formula I also includes compounds of Formula VI: tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula la.
  • compositions comprising at least one compound chosen from the novel compounds disclosed herein, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, which compositions may further include at least one additional active pharmaceutical ingredient.
  • the at least one additional active pharmaceutical ingredient is at least one other CFTR modulator.
  • the at least one other CFTR modulator is selected from CFTR potentiators and CFTR modulators.
  • another aspect of the disclosure provides methods of treating the CFTR- mediated disease cystic fibrosis comprising administering at least one compound chosen from the novel compounds disclosed herein, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, optionally as part of a pharmaceutical composition comprising at least one additional component, to a subject in need thereof.
  • the at least one additional active pharmaceutical ingredient in the methods of treating disclosed herein is at least one other CFTR modulator.
  • the at least one other CFTR modulator is selected from CFTR potentiators and CFTR correctors.
  • the pharmaceutical compositions of the disclosure comprise at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • compositions comprising at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing may optionally further comprise (a) at least one (i.e., one or more) compound chosen from (R)-1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2- methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (tezacaftor), 3-(6-(1-(2,2- difluorobenzo[d][1,3]dioxol-5
  • Another aspect of the disclosure provides methods of treating the CFTR-mediated disease cystic fibrosis comprising administering to a patient in need thereof at least one compound chosen from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, and optionally further administering one or more additional CFTR modulating agents selected from tezacaftor, ivacaftor, and lumacaftor.
  • compounds of the disclosure e.g., compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing
  • pharmaceutical compositions comprising those compounds, and optionally further comprising one or more CFTR modulating agents
  • the one or more additional CFTR modulating agents are selected from CFTR potentiators.
  • the one or more additional CFTR modulating agents are selected from CFTR correctors. In some embodiments, the one or more additional CFTR modulating agents are selected from tezacaftor, lumacaftor, ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.
  • a further aspect of the disclosure provides intermediates and methods for making the compounds and compositions disclosed herein.
  • “Tezacaftor” as used herein, refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N- (1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5- yl)cyclopropanecarboxamide, which can be depicted with the following structure: .
  • Tezacaftor may be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative.
  • Tezacaftor and methods of making and using tezacaftor are disclosed in WO 2010/053471, WO 2011/119984, WO 2011/133751, WO 2011/133951, WO 2015/160787, and US 2009/0131492, each of which is incorporated herein by reference.
  • Ivacaftor refers to N-[2,4-bis(1,1-dimethylethyl)- 5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, which is depicted by the structure: .
  • Ivacaftor may also be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative.
  • Ivacaftor and methods of making and using ivacaftor are disclosed in WO 2006/002421, WO 2007/079139, WO 2010/108162, and WO 2010/019239, each of which is incorporated herein by reference.
  • a deuterated derivative of ivacaftor (deutivacaftor) is employed in the compositions and methods disclosed herein.
  • a chemical name for deutivacaftor is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide, as depicted by the structure: .
  • Deutivacaftor may be in the form of a further deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative.
  • Deutivacaftor and methods of making and using deutivacaftor are disclosed in WO 2012/158885, WO 2014/078842, and US Patent No.8,865,902, each of which is incorporated herein by reference.
  • “Lumacaftor” as used herein refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which is depicted by the chemical structure: .
  • Lumacaftor may be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative.
  • Lumacaftor and methods of making and using lumacaftor are disclosed in WO 2007/056341, WO 2009/073757, and WO 2009/076142, each of which is incorporated herein by reference.
  • alkyl refers to a saturated or partially saturated, branched, or unbranched aliphatic hydrocarbon containing carbon atoms (such as, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms) in which one or more adjacent carbon atoms is interrupted by a double (alkenyl) or triple (alkynyl) bond. Alkyl groups may be substituted or unsubstituted.
  • haloalkyl group refers to an alkyl group substituted with one or more halogen atoms, e.g., fluoroalkyl, which refers to an alkyl group substituted with one or more fluorine atoms.
  • alkoxy refers to an alkyl or cycloalkyl covalently bonded to an oxygen atom. Alkoxy groups may be substituted or unsubstituted.
  • haloalkoxyl group refers to an alkoxy group substituted with one or more halogen atoms.
  • cycloalkyl refers to a cyclic, bicyclic, tricyclic, or polycyclic non- aromatic hydrocarbon groups having 3 to 12 carbons (such as, for example 3-10 carbons) and may include one or more unsaturated bonds.
  • Cycloalkyl groups encompass monocyclic, bicyclic, tricyclic, bridged, fused, and spiro rings, including mono spiro and dispiro rings.
  • Non- limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, dispiro[2.0.2.1]heptane, and spiro[2,3]hexane. Cycloalkyl groups may be substituted or unsubstituted.
  • aryl as used herein, is a functional group or substituent derived from an aromatic ring and encompasses monocyclic aromatic rings and bicyclic, tricyclic, and fused ring systems wherein at least one ring in the system is aromatic.
  • Non-limiting examples of aryl groups include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalenyl.
  • the term “heteroaryl ring,” as used herein, refers to an aromatic ring comprising at least one ring atom that is a heteroatom, such as O, N, or S.
  • Heteroaryl groups encompass monocyclic rings and bicyclic, tricyclic, bridged, fused, and spiro ring systems (including mono spiro and dispiro rings) wherein at least one ring in the system is aromatic.
  • Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole, and indoline.
  • heteroaryl ring encompasses heteroaryl rings with various oxidation states, such as heteroaryl rings containing N-oxides and sulfoxides.
  • Non-limiting examples of such heteroaryl rings include pyrimidine A-oxides, quinoline A-oxides, thiophene S-oxides, and pyrimidine A-oxides.
  • heterocyclyl ring refers to a non-aromatic hydrocarbon containing 3 to 12 atoms in a ring (such as, for example 3-10 atoms) comprising at least one ring atom that is a heteroatom, such as O, N, or S, and may include one or more unsaturated bonds.
  • heterocyclyl rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including mono spiro and dispiro rings.
  • Substituted indicates that at least one hydrogen of the “substituted” group is replaced by a substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at each position.
  • Non-limiting examples of protecting groups for nitrogen include, for example, t-butyl carbamate (Boc), benzyl (Bn), para-methoxybenzyl (PMB), tetrahydropyranyl (THP), 9- fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), methyl carbamate, ethyl carbamate, 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), allyl carbamate (Aloe or Alloc), formamide, acetamide, benzamide, allylamine, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide.
  • a comprehensive list of nitrogen protecting groups can be found in Wuts, P. G. M. “Greene’s Protective Groups in Organic Synthesis: Fifth Edition,” 2014,
  • deuterated derivative(s) refers to a compound having the same chemical structure as a reference compound, with one or more hydrogen atoms replaced by a deuterium atom.
  • the one or more hydrogens replaced by deuterium are part of an alkyl group.
  • the one or more hydrogens replaced by deuterium are part of a methyl group.
  • CFTR cystic fibrosis transmembrane conductance regulator.
  • CFTR modulator refers to a compound that increases the activity of CFTR. The increase in activity resulting from a CFTR modulator includes, but is not limited to, compounds that correct, potentiate, stabilize, and/or amplify CFTR.
  • corrector and “CFTR corrector” are used interchangeably and refer to a compound that facilitates the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface. The novel compounds disclosed herein are CFTR correctors.
  • Tezacaftor and lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof as referenced herein, are correctors.
  • the terms “potentiator” and “CFTR potentiator” refer to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport.
  • Ivacaftor, deutivacaftor, and (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, as referenced herein, are CFTR potentiators.
  • the combination will typically but not necessarily include a CFTR potentiator, such as, e.g., ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, or a deuterated derivative or pharmaceutically acceptable salt of any of the foregoing.
  • a CFTR potentiator such as, e.g., ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, or
  • a combination of at least one compound selected from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing will include a potentiator selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, or deuterated derivatives or pharmaceutically acceptable salts thereof and may
  • a reference to “Compounds 1–1924” herein is intended to represent a reference to each of Compounds 1 through 1294 individually or a reference to groups of compounds, such as, e.g., Compounds 1-1193, Compounds 1194-1294, and Compounds 1295-1972.
  • the term “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refers to a biologically active compound.
  • the terms “patient” and “subject” are used interchangeably and refer to an animal, including a human.
  • an effective dose and “effective amount” are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in CF or a symptom of CF, or lessening the severity of CF or a symptom of CF).
  • the exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
  • the terms “treatment,” “treating,” and the like generally mean the improvement in one or more symptoms of CF or lessening the severity of CF or one or more symptoms of CF in a subject.
  • Treatment includes, but is not limited to, the following: increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and/or liver function, reduction of chest infections, and/or reductions in coughing or shortness of breath. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.
  • references herein to methods of treatment e.g., methods of treating a CFTR mediated disease or a method of treating cystic fibrosis using one or more compounds of the disclosure optionally in combination with one or more additional CFTR modulating agents (e.g., a compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, optionally in combination with one or more additional CFTR modulating agents) should also be interpreted as references to: - one or more compounds (e.g., a compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194
  • references herein to methods of treatment e.g., methods of treating a CFTR mediated disease or a method of treating cystic fibrosis using a pharmaceutical composition of the disclosure (e.g., a pharmaceutical composition comprising at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and optionally further comprising one or more additional CFTR modulating agents
  • a pharmaceutical composition e.g., a pharmaceutical composition comprising at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 11
  • the term “in combination with,” when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other.
  • the terms “about” and “approximately” may refer to an acceptable error for a particular value as determined by one of skill in the art, which depends in part on how the values are measured or determined. In some embodiments, the terms “about” and “approximately” mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.
  • the term “solvent” refers to any liquid in which the product is at least partially soluble (solubility of product >1 g/L).
  • room temperature or “ambient temperature” means 15 °C to 30 °C.
  • certain compounds of this disclosure may exist as separate stereoisomers or enantiomers and/or mixtures of those stereoisomers or enantiomers.
  • Certain compounds disclosed herein may exist as tautomers and both tautomeric forms are intended, even though only a single tautomeric structure is depicted.
  • minimal function (MF) mutations refer to CFTR gene mutations associated with minimal CFTR function (little-to-no functioning CFTR protein) and include, for example, mutations associated with severe defects in ability of the CFTR channel to open and close, known as defective channel gating or “gating mutations”; mutations associated with severe defects in the cellular processing of CFTR and its delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; and mutations associated with severe defects in channel conductance.
  • the term “pharmaceutically acceptable salt” refers to a salt form of a compound of this disclosure, wherein the salt is nontoxic.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • a “free base” form of a compound, for example, does not contain an ionically bonded salt.
  • One of ordinary skill in the art would recognize that, when an amount of “a compound or a pharmaceutically acceptable salt thereof” is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. It is noted that the disclosed amounts of the compounds or their pharmaceutically acceptable salts thereof herein are based upon their free base form.
  • Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19.
  • Table 1 of that article provides the following pharmaceutically acceptable salts: Table 1:
  • Non-limiting examples of pharmaceutically acceptable acid addition salts include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed by using other methods used in the art, such as ion exchange.
  • Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • any of the novel compounds disclosed herein such as, for example, compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1- 1193, Compounds 1194-1294, Compounds 1295-1972, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, can act as a CFTR modulator, i.e., it modulates CFTR activity in the body.
  • a CFTR mutation may affect the CFTR quantity, i.e., the number of CFTR channels at the cell surface, or it may impact CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations affecting CFTR quantity include mutations that cause defective synthesis (Class I defect), mutations that cause defective processing and trafficking (Class II defect), mutations that cause reduced synthesis of CFTR (Class V defect), and mutations that reduce the surface stability of CFTR (Class VI defect). Mutations that affect CFTR function include mutations that cause defective gating (Class III defect) and mutations that cause defective conductance (Class IV defect). Some CFTR mutations exhibit characteristics of multiple classes. Certain mutations in the CFTR gene result in cystic fibrosis.
  • the disclosure provides methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering to the patient an effective amount of any of the novel compounds disclosed herein, such as, for example, compounds of Formula I, compounds of any of Formulae la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, alone or in combination with another active ingredient, such as one or more CFTR modulating agents.
  • compounds of Formula I compounds of any of Formulae la, lb, Ila, lib, III, IV, V, and VI
  • Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972 Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972
  • tautomers thereof deuterated
  • the one or more CFTR modulating agents are selected from ivacaftor, deutivacaftor, lumacaftor, and tezacaftor.
  • the patient has an F508del/minimal function (MF) genotype, F508del/F508del genotype (homozygous for the F508del mutation), F508del/gating genotype, or F508del/residual function (RF) genotype.
  • MF F508del/minimal function
  • F508del/F508del genotype homozygous for the F508del mutation
  • F508del/gating genotype F508del/gating genotype
  • F508del/residual function (RF) genotype F508del/residual function
  • the patient is heterozygous and has one F508del mutation.
  • the patient is homozygous for the N1303K mutation
  • 5 mg to 500 mg of a compound disclosed herein, a tautomer thereof, deuterated derivatives of the compound and tautomer, or a pharmaceutically acceptable salt of any of the foregoing are administered daily.
  • the patient has at least one F508del mutation in the CFTR gene.
  • the patient has a CFTR gene mutation that is responsive to a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the invention based on in vitro data.
  • the patient is heterozygous and has an F508del mutation on one allele and a mutation on the other allele selected from Table 2:
  • the disclosure also is directed to methods of treatment using isotope-labelled compounds of the afore-mentioned compounds, or pharmaceutically acceptable salts thereof, wherein the formula and variables of such compounds and salts are each and independently as described above or any other embodiments described above, provided that one or more atoms therein have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally (isotope labelled).
  • isotopes which are commercially available and suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • the isotope-labelled compounds and salts can be used in a number of beneficial ways. They can be suitable for medicaments and/or various types of assays, such as substrate tissue distribution assays. For example, tritium ( 3 H)- and/or carbon-14 ( 14 C)-labelled compounds are particularly useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.
  • deuterium ( 2 H)-labelled ones are therapeutically useful with potential therapeutic advantages over the non- 2 H-labelled compounds.
  • deuterium ( 2 H)-labelled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labelled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which could be desired.
  • the isotope-labelled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.
  • the isotope-labelled compounds and salts are deuterium ( 2 H)- labelled ones.
  • the isotope-labelled compounds and salts are deuterium ( 2 H)-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium. In chemical structures, deuterium is represented as “D.”
  • deuterium is represented as “D.”
  • concentration of the isotope(s) (e.g., deuterium) incorporated into the isotope- labelled compounds and salt of the disclosure may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of the disclosure is denoted as deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • One aspect disclosed herein provides methods of treating cystic fibrosis and other CFTR mediated diseases using any of the novel compounds disclosed herein, such as, for example, compounds of Formula I, compounds of any of Formulae la, lb, Ila, lib, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient.
  • At least one additional active pharmaceutical ingredient is selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, and antiinflammatory agents.
  • the additional therapeutic agent is an antibiotic.
  • antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin.
  • the additional agent is a mucolyte.
  • mucolytes useful herein include Pulmozyme®.
  • the additional agent is a bronchodilator.
  • bronchodilators include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate.
  • the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce the inflammation in the lungs.
  • agents useful herein include ibuprofen, docosahexanoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.
  • the additional agent is a nutritional agent.
  • Exemplary nutritional agents include pancrelipase (pancreatic enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation.
  • the additional nutritional agent is pancrelipase.
  • at least one additional active pharmaceutical ingredient is selected from CFTR modulating agents.
  • the at least one additional active pharmaceutical ingredient is selected from CFTR potentiators.
  • the potentiator is selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.
  • the at least one additional active pharmaceutical ingredient is chosen from CFTR correctors.
  • the correctors are selected from lumacaftor, tezacaftor, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.
  • the at least one additional active pharmaceutical ingredient is chosen from (a) tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and/or (b) ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.
  • the combination therapies provided herein comprise (a) a compound selected from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; and (b) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; or (c) at least one compound selected from ivacaftor, deutivacaftor, (6R,12R)-17- amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-o
  • the combination therapies provided herein comprise (a) at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor and pharmaceutically acceptable salts thereof; and (c) at least one compound selected from ivacaftor, deutivacaftor, and pharmaceutically acceptable salts thereof.
  • the combination therapies provided herein comprise (a) at least one compound chosen from compounds of Formula I, compounds of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and/or (c) at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from tezacaftor and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from ivacaftor and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, deuterated derivatives thereof, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from deutivacaftor and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194- 1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from (6R,12R)-17-amino-12-methyl- 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194- 1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from (6R,12R)-17-amino-12-methyl- 6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered once daily.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound chosen from tezacaftor and pharmaceutically acceptable salts thereof, and at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof are administered twice daily.
  • Compounds of Formula I compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, tezacaftor, lumacaftor, ivacaftor, deutivacaftor, (6R,12R)-17-amino-12- methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol, and their deuterated derivatives and pharmaceutically acceptable salts thereof can be administered in a single pharmaceutical composition or separate pharmaceutical compositions.
  • Such pharmaceutical compositions can be administered once daily or multiple times daily, such as twice daily.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; and at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.
  • At least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutical
  • the second pharmaceutical composition comprises a half of a daily dose of said at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and the other half of the daily dose of said at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.
  • the first pharmaceutical composition is administered to the patient twice daily.
  • the first pharmaceutical composition is administered once daily. In some embodiments, the first pharmaceutical composition is administered once daily and, when the first composition comprises ivacaftor, a second composition comprising only ivacaftor is administered once daily.
  • Any suitable pharmaceutical compositions can be used for compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, tezacaftor, ivacaftor, deutivacaftor, lumacaftor and tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • Some exemplary pharmaceutical compositions for tezacaftor and its pharmaceutically acceptable salts can be found in WO 2011/119984 and WO 2014/014841, all of which is incorporated herein by reference.
  • Some exemplary pharmaceutical compositions for ivacaftor and its pharmaceutically acceptable salts can be found in WO 2007/134279, WO 2010/019239, WO 2011/019413, WO 2012/027731, and WO 2013/130669, and some exemplary pharmaceutical compositions for deutivacaftor and its pharmaceutically acceptable salts can be found in US 8,865,902, US 9,181,192, US 9,512,079, WO 2017/053455, and WO 2018/080591, all of which are incorporated herein by reference.
  • compositions for lumacaftor and its pharmaceutically acceptable salts can be found in WO 2010/037066, WO 2011/127421, and WO 2014/071122, all of which are incorporated herein by reference.
  • Pharmaceutical Compositions [00102] Another aspect of the disclosure provides a pharmaceutical composition comprising at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier.
  • the disclosure provides pharmaceutical compositions comprising at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient.
  • the at least one additional active pharmaceutical ingredient is a CFTR modulator.
  • the at least one additional active pharmaceutical ingredient is a CFTR corrector.
  • the at least one additional active pharmaceutical ingredient is a CFTR potentiator.
  • the pharmaceutical composition comprises at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and one of which is a CFTR potentiator.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from tezacaftor and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing, and (c) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formula I, compounds of any of Formulae Ia, Ib, IIa, IIb, III, IV, V, and VI, Compounds 1-1193, Compounds 1194-1294, Compounds 1295-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing, (c) at least one compound chosen from lumacaftor and
  • any pharmaceutical composition disclosed herein may comprise at least one pharmaceutically acceptable carrier.
  • the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants.
  • the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.
  • the pharmaceutical compositions described herein are useful for treating cystic fibrosis and other CFTR mediated diseases.
  • pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier.
  • the at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles.
  • the at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
  • Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt,
  • Formula I encompasses compounds falling within the following structure: and includes tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; Ring B is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; V is selected from O and NH; W 1 is selected from N and CH; W 2 is selected from N and CH, provided that at least one of W 1 and W 2 is N; Z is selected from O, NR ZN , and C(R ZC
  • a compound of Formula Ia a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring A is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; Ring B is selected from: ⁇ C 6 -C 10 aryl, ⁇ C 3 -C 10 cycloalkyl, ⁇ 3- to 10-membered heterocyclyl, and ⁇ 5- to 10-membered heteroaryl; V is selected from O and NH; W 1 is selected from N and CH; W 2 is selected from N and CH; provided that at least one of W 1 and W 2 is N; Z is selected from O, NR ZN , and C(R ZC ) 2 , provided that when L 2 is absent, Z is C(R ZC ) 2 ; each L
  • Z is selected from NR ZN and C(R ZC ) 2 , provided that when L 2 is absent, Z is C(R ZC ) 2 .
  • the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 10 wherein each L 1 is C(R L1 ) 2 .
  • each R 3 is independently selected from C 1 -C 6 alkyl.
  • each R 5 is independently selected from: ⁇ hydrogen, ⁇ hydroxyl, ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl, and ⁇ C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl. 19.
  • R YN is selected from: ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o oxo, o cyano, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy, o N(R N ) 2 , o SO 2 Me, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N ) 2 , ⁇ C 1 -C 6 fluoroalkyl, ⁇ C 1 -C 6 alkoxy, and ⁇ COOH, o C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from: ⁇ hal
  • each R ZC is hydrogen, or two R ZC are taken together to form an oxo group.
  • 21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 20, wherein each R L1 is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, o oxo, o N(R N ) 2 , o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 fluoroalkyl, and o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 al
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 8 alkyl optionally substituted with 1-3 groups independently selected from: o oxo, o hydroxyl, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, o 3- to 14-membered heterocyclyl, o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C 1 -
  • a compound of Formula Ib a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, Ring B, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R YN are defined as according to embodiment 1a.
  • each L 1 is C(R L1 ) 2 .
  • 37. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 25 to 36, wherein each R 3 is methyl. 38.
  • each R 5 is independently selected from: ⁇ hydrogen, ⁇ hydroxyl, ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl, ⁇ C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl, 42.
  • R YN is selected from: ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o oxo, o cyano, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy, o N(R N ) 2 , o SO 2 Me, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N ) 2 , ⁇ C 1 -C 6 fluoroalkyl, ⁇ C 1 -C 6 alkoxy, and ⁇ COOH, o C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from: ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o o
  • each R ZC is hydrogen, or two R ZC are taken together to form an oxo group
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, o oxo, o N(R N ) 2 , o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 fluoroalkyl, and o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C 1 -C
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C1-C8 alkyl optionally substituted with 1-3 groups independently selected from: o oxo, o hydroxyl, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, o 3- to 14-membered heterocyclyl, o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C 1
  • Ring B, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R YN are defined as according to embodiment 1a.
  • each R 5 is independently selected from: ⁇ hydrogen, ⁇ hydroxyl, ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl, ⁇ C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl, 62.
  • R YN is selected from: ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o oxo, o cyano, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy, o N(R N ) 2 , o SO 2 Me, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N ) 2 , ⁇ C 1 -C 6 fluoroalkyl, ⁇ C 1 -C 6 alkoxy, and ⁇ COOH, o C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from: ⁇
  • each R ZC is hydrogen, or two R ZC are taken together to form an oxo group; 64.
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, o oxo, o N(R N ) 2 , o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 fluoroalkyl, and o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C 1
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C1-C8 alkyl optionally substituted with 1-3 groups independently selected from: o oxo, o hydroxyl, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, o 3- to 14-membered heterocyclyl, o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C 1
  • a compound of Formula IIb a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, W 1 , W 2 , Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R YN are defined as according to embodiment 1a.
  • Z is selected from NR ZN and C(R ZC ) 2 , provided that when L 2 is absent, Z is C(R ZC ) 2 .
  • 74 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 68 to 73, wherein each L 1 is C(R L1 ) 2 .
  • 75 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 68 to 74, wherein L 2 is absent.
  • each R 3 is independently selected from C 1 -C 6 alkyl. 77.
  • R 4 is selected from hydrogen and methyl. 80.
  • each R 5 is independently selected from: ⁇ hydrogen, ⁇ hydroxyl, ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl, ⁇ C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl, 82.
  • R YN is selected from: ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o oxo, o cyano, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy, o N(R N ) 2 , o SO 2 Me, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N ) 2 , ⁇ C 1 -C 6 fluoroalkyl, ⁇ C 1 -C 6 alkoxy, and ⁇ COOH, o C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:
  • each R ZC is hydrogen, or two R ZC are taken together to form an oxo group; 84.
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C1-C8 alkyl optionally substituted with 1-3 groups independently selected from: o oxo, o hydroxyl, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, o 3- to 14-membered heterocyclyl, o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected
  • a compound of Formula III a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein W 1 , W 2 , Z, L 1 , L 2 , R 4 , R 5 , and R YN are defined as according to embodiment 1a. 89.
  • each R 5 is independently selected from: ⁇ hydrogen, ⁇ hydroxyl, ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl, ⁇ C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl, 96.
  • R YN is selected from: ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o oxo, o cyano, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy, o N(R N ) 2 , o SO 2 Me, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N ) 2 , ⁇ C 1 -C 6 fluoroalkyl, ⁇ C 1 -C 6 alkoxy, and ⁇ COOH, o C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from: ⁇
  • each R ZC is hydrogen, or two R ZC are taken together to form an oxo group; 98.
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 8 alkyl optionally substituted with 1-3 groups independently selected from: o oxo, o hydroxyl, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, o 3- to 14-membered heterocyclyl, o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected
  • a compound of Formula IV a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Z, L 1 , L 2 , R 4 , R 5 , and R YN are defined as according to embodiment 1a. 103.
  • 104 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 102 or 103, wherein each L 1 is C(R L1 ) 2 .
  • each R 5 is independently selected from: ⁇ hydrogen, ⁇ hydroxyl, ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl, ⁇ C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl, 109.
  • R YN is selected from: ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o oxo, o cyano, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy, o N(R N ) 2 , o SO 2 Me, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N ) 2 , ⁇ C 1 -C 6 fluoroalkyl, ⁇ C 1 -C 6 alkoxy, and ⁇ COOH, o C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:
  • each R ZC is hydrogen, or two R ZC are taken together to form an oxo group; 111.
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C1-C8 alkyl optionally substituted with 1-3 groups independently selected from: o oxo, o hydroxyl, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, o 3- to 14-membered heterocyclyl, o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected
  • a compound of Formula V a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Z, L 1 , L 2 , R 4 , R 5 , and R YN are defined as according to embodiment 1a.
  • 116. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 115, wherein Z is selected from NR ZN and C(R ZC ) 2 , provided that when L 2 is absent, Z is C(R ZC ) 2 .
  • 117. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 115 or 116, wherein each L 1 is C(R L1 ) 2 .
  • each R 5 is independently selected from: ⁇ hydrogen, ⁇ hydroxyl, ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl, ⁇ C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl, 122.
  • R YN is selected from: ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o oxo, o cyano, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy, o N(R N ) 2 , o SO 2 Me, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N ) 2 , ⁇ C 1 -C 6 fluoroalkyl, ⁇ C 1 -C 6 alkoxy, and ⁇ COOH, o C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:
  • each R ZC is hydrogen, or two R ZC are taken together to form an oxo group; 124.
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C1-C8 alkyl optionally substituted with 1-3 groups independently selected from: o oxo, o hydroxyl, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, o 3- to 14-membered heterocyclyl, o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups
  • a compound of Formula VI a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein L 1 , R 4 , R 5 , and R YN are defined as according to embodiment 1a. 129.
  • each R 5 is independently selected from: ⁇ hydrogen, ⁇ hydroxyl, ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from C 3 -C 10 cycloalkyl, ⁇ C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl, 133.
  • R YN is selected from: ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o hydroxyl, o oxo, o cyano, o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from halogen and C 1 -C 6 alkoxy, o N(R N ) 2 , o SO 2 Me, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from: ⁇ C 1 -C 6 alkyl optionally substituted with 1-3 groups independently selected from oxo and N(R N ) 2 , ⁇ C 1 -C 6 fluoroalkyl, ⁇ C 1 -C 6 alkoxy, and ⁇ COOH, o C 6 -C 10 aryl optionally substituted with 1-3 groups independently selected from:
  • each R L1 is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 9 alkyl optionally substituted with 1-3 groups independently selected from: o halogen, o hydroxyl, o oxo, o N(R N ) 2 , o C 1 -C 6 alkoxy optionally substituted with 1-3 groups independently selected from C 6 -C 10 aryl, o C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 fluoroalkyl, and o 3- to 10-membered heterocyclyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and oxo), ⁇ C 6 -C 10 aryl optionally substituted with 1-4 groups independently selected from: o halogen,
  • each R N is independently selected from: ⁇ hydrogen, ⁇ C 1 -C 8 alkyl optionally substituted with 1-3 groups independently selected from: o oxo, o hydroxyl, o C 1 -C 6 alkoxy, o -(O) 0-1 -(C 3 -C 10 cycloalkyl), o C 6 -C 10 aryl, o 3- to 14-membered heterocyclyl, o 5- to 14-membered heteroaryl optionally substituted with 1-4 groups independently selected from C 1 -C 6 alkyl, ⁇ C 3 -C 10 cycloalkyl optionally substituted with 1-3 groups independently selected from C 1 -C 6 alkyl, and ⁇ 3- to 10-membered heterocyclyl; or two R N on the same nitrogen atom are taken together with the nitrogen to which they are bonded to form a
  • a pharmaceutical composition comprising the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 138, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of embodiment 140 wherein the one or more additional therapeutic agents is selected from mucolytic agents, bronchodilators, antibiotics, anti- infective agents, and anti-inflammatory agents.
  • the one or more additional therapeutic agent is an antibiotic selected from tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin.
  • TIP tobramycin inhaled powder
  • aztreonam including the aerosolized form of aztreonam
  • amikacin including liposomal formulations thereof
  • ciprofloxacin including formulations thereof suitable for administration by inhalation
  • levoflaxacin including aerosolized formulation
  • the pharmaceutical composition of embodiment 140, wherein the one or more additional therapeutic agent is one or more CFTR modulating agents.
  • the one or more CFTR modulating agents are selected from CFTR potentiators.
  • the one or more CFTR modulating agents are selected from CFTR correctors.
  • the one or more CFTR modulating agents comprises at least one CFTR potentiator and at least one CFTR corrector. 147.
  • composition of any one of embodiment 143-146, wherein the one or more CFTR modulating agents are selected from (a) tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (b) ivacaftor, deutivacaftor, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. 148.
  • composition comprises tezacaftor and ivacaftor.
  • composition comprises tezacaftor and deutivacaftor.
  • composition comprises tezacaftor and (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca- 1 ( 18), 2, 4, 14, 16-pentaen-6-ol .
  • composition of any one of embodiment 143-147, wherein the composition comprises lumacaftor and ivacaftor.
  • composition of any one of embodiment 143-147, wherein the composition comprises lumacaftor and deutivacaftor.
  • composition of any one of embodiment 143-147, wherein the composition comprises lumacaftor and (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca- 1 ( 18), 2, 4, 14, 16-pentaen-6-ol .
  • a method of treating cystic fibrosis comprising administering to a patient in need thereof the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 138, or a pharmaceutical composition according to any one of embodiments 139 to 154.
  • the one or more additional therapeutic agent(s) is a compound selected from tezacaftor, ivacaftor, deutivacaftor, lumacaftor, and pharmaceutically acceptable salts thereof.
  • the one or more additional therapeutic agents are tezacaftor and ivacaftor.
  • the one or more additional therapeutic agents are tezacaftor and deutivacaftor.
  • the one or more additional therapeutic agents are tezacaftor and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol.
  • the one or more additional therapeutic agents are lumacaftor and ivacaftor.
  • the one or more additional therapeutic agents are lumacaftor and deutivacaftor. 169.
  • 172. A compound selected from Compounds 1-1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.
  • a pharmaceutical composition comprising a compound selected from Compounds 1- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a deuterated derivative of a compound selected from Compounds 1-1972 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from Compounds 1-1972 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound selected from Compounds 1- 1972 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition composition comprising (a) a deuterated derivative of a compound selected from Compounds 1-1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a deuterated derivative of a compound selected from Compounds 1-1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; (c) a CRTR potentiator; and (d) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a deuterated derivative of a compound selected from Compounds 1-1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound selected from Compounds 1- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing and a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising a deuterated derivative of a compound selected from Compounds 1-1972 and a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from Compounds 1-1972 and a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising a compound selected from Compounds 1- 1972 and a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical comprising (a) a deuterated derivative of a compound selected from Compounds 1-1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972; (b) a CFTR potentiator; and (c) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a deuterated derivative of a compound selected from Compounds 1-1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972; (b) an additional CFTR corrector; and (c) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis. 208.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) an additional CFTR corrector; (c) a CRTR potentiator; and (d) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis. 209.
  • a pharmaceutical composition comprising (a) a deuterated derivative of a compound selected from Compounds 1-1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis. 210.
  • a pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from Compounds 1-1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • a pharmaceutical composition comprising (a) a compound selected from Compounds 1- 1972; (b) an additional CFTR corrector; (c) a CFTR potentiator; and (d) a pharmaceutically acceptable carrier for use in a method of treating cystic fibrosis.
  • NMR (1D & 2D) spectra were also recorded on a Bruker AVNEO 400 MHz spectrometer operating at 400 MHz and 100 MHz respectively equipped with a 5 mm multinuclear Iprobe.
  • NMR spectra were also recorded on a Varian Mercury NMR instrument at 300 MHz for 1 H using a 45 degree pulse angle, a spectral width of 4800 Hz and 28860 points of acquisition. FID were zero-filled to 32k points and a line broadening of 0.3Hz was applied before Fourier transform.19F NMR spectra were recorded at 282 MHz using a 30 degree pulse angle, a spectral width of 100 kHz and 59202 points were acquired.
  • FID were zero-filled to 64k points and a line broadening of 0.5 Hz was applied before Fourier transform.
  • NMR spectra were also recorded on a Bruker Avance III HD NMR instrument at 400 MHz for 1 H using a 30 degree pulse angle, a spectral width of 8000 Hz and 128k points of acquisition. FID were zero-filled to 256k points and a line broadening of 0.3Hz was applied before Fourier transform.
  • 19 F NMR spectra were recorded at 377 MHz using a 30 deg pulse angle, a spectral width of 89286 Hz and 128k points were acquired. FID were zero-filled to 256k points and a line broadening of 0.3 Hz was applied before Fourier transform.
  • NMR spectra were also recorded on a Bruker AC 250MHz instrument equipped with a: 5mm QNP(H1/C13/F19/P31) probe (type: 250-SB, s#23055/0020) or on a Varian 500MHz instrument equipped with a ID PFG, 5 mm, 50-202/500 MHz probe (model/part# 99337300).
  • Final purity of compounds was determined by reversed phase UPLC using an Acquity UPLC BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 3.0 minutes.
  • Mobile phase A H 2 O (0.05 % CF 3 CO 2 H).
  • Mobile phase B CH 3 CN (0.035 % CF 3 CO 2 H).
  • Final purity was calculated by averaging the area under the curve (AUC) of two UV traces (220 nm, 254 nm).
  • AUC area under the curve
  • Low-resolution mass spectra were reported as [M+1] + species obtained using a single quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source capable of achieving a mass accuracy of 0.1 Da and a minimum resolution of 1000 (no units on resolution) across the detection range.
  • ESI electrospray ionization
  • Optical purity of methyl (2S)-2,4-dimethyl-4-nitro-pentanoate was determined using chiral gas chromatography (GC) analysis on an Agilent 7890A/MSD 5975C instrument, using a Restek Rt- ⁇ DEXcst (30 m x 0.25 mm x 0.25 ⁇ m_df) column, with a 2.0 mL/min flow rate (H 2 carrier gas), at an injection temperature of 220 °C and an oven temperature of 120 °C, 15 minutes.
  • GC chiral gas chromatography
  • LC method A Analytical reverse phase UPLC using an Acquity UPLC BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 3.0 minutes.
  • Mobile phase A H 2 O (0.05 % CF 3 CO 2 H).
  • Mobile phase B CH 3 CN (0.035 % CF 3 CO 2 H).
  • LC method C Kinetex C184.6 x 50 mm 2.6 ⁇ m.
  • LC method G Symmetry, 4.6 x 75 mm 3.5 ⁇ m. Temp: 45 °C , Flow: 2.0 mL/min, Run Time: 8 min.
  • Mobile Phase Initial 95% H 2 O (0.1% Formic Acid) and 5% CH 3 CN (0.1% FA) linear gradient to 95% CH 3 CN (0.1% formic acid) for 6.0 min then hold at 95% CH 3 CN (0.1% formic acid) for 2.0 min.
  • LC method H Kinetex C184.6 X 50 mm 2.6 um.
  • LC method J Reverse phase UPLC using an Acquity UPLC BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes.
  • Mobile phase A H 2 O (0.05 % NH 4 HCO 2 ).
  • Mobile phase B CH 3 CN.
  • LC method K Kinetex Polar C183.0 x 50 mm 2.6 ⁇ m, 3 min, 5-95% ACN in H 2 O (0.1% Formic Acid) 1.2 ml/min.
  • LC method Q Reversed phase UPLC using an Acquity UPLC BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002350), and a dual gradient run from 30- 99% mobile phase B over 2.9 minutes.
  • Mobile phase A H 2 O (0.05 % CF 3 CO 2 H).
  • Mobile phase B CH 3 CN (0.035 % CF 3 CO 2 H).
  • LC method S Merckmillipore Chromolith SpeedROD C18 column (50 x 4.6 mm) and a dual gradient run from 5 - 100% mobile phase B over 12 minutes.
  • Mobile phase A water (0.1 % CF 3 CO 2 H).
  • Mobile phase B acetonitrile (0.1 % CF 3 CO 2 H).
  • LC method T Merckmillipore Chromolith SpeedROD C18 column (50 x 4.6 mm) and a dual gradient run from 5 - 100% mobile phase B over 6 minutes.
  • Mobile phase A water (0.1 % CF 3 CO 2 H).
  • Mobile phase B acetonitrile (0.1 % CF 3 CO 2 H).
  • LC method U Kinetex Polar C183.0 x 50 mm 2.6 ⁇ m, 6 min, 5-95% ACN in H 2 O (0.1% Formic Acid) 1.2 mL/min.
  • LC method V Acquity UPLC BEH C 18 column (50 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002350), and a dual gradient run from 1-30% mobile phase B over 2.9 minutes.
  • Mobile phase A H20 (0.05 % CF 3 CO 2 H).
  • Mobile phase B CH 3 CN (0.035 % CF 3 CO 2 H).
  • LC method W water Cortex 2.7 ⁇ C18 (3.0 mm x 50 mm), Temp: 55 °C; Flow: 1.2 mL/min; mobile phase: 100% water with 0.1% trifluoroacetic(TFA) acid then 100% acetonitrile with 0.1% TFA acid, grad:5% to 100% B over 4 min, with stay at 100% B for 0.5min, equilibration to 5% B over 1.5min.
  • LC method X UPLC Luna C18(2) 50 x 3mm 3 ⁇ m. run: 2.5 min.
  • LC method 1A Reversed phase UPC2 using a Viridis BEH 2-Ethylpyridine column (150 ⁇ 2.1 mm, 3.5 ⁇ m particle) made by Waters (pn: 186006655), and a dual gradient run from 5-80% mobile phase B over 4.5 minutes.
  • Mobile phase A CO 2 .
  • Mobile phase B MeOH (20 mM NH 3 ).
  • GC method 1B Column SPB-130 m x 0.32 mm x 0.25 um.
  • Control mode head pressure 100 kPa.
  • Split ratio mode 10.0.
  • Carrier gas hydrogen.
  • Injector temperature 150 °C.
  • Detector temperature 250 °C.
  • Oven temperature isotherm at 40 °C for 1 min, then linear heating at 10 C/min until 100 °C, then 20 °C/min until 220 °C then isotherm 220 °C for 4 min. Run time 17.0 minutes.
  • LC method 1C Luna C18(2) 3.0 x 50 mm 3 ⁇ m, run: 5 min.
  • LC method 1E reversed phase UPLC using an Acquity UPLC BEH C18 column (30 ⁇ 2.1 mm, 1.7 ⁇ m particle) made by Waters (pn: 186002349), and a dual gradient run from 1- 99% mobile phase B over 2.9 minutes.
  • Mobile phase A H20 (5 mM NH 4 OH).
  • Mobile phase B CH 3 CN.
  • Step 2 tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6- dimethylphenyl)pyrimidin-2-yl]carbamate. [00143] All solvents were degassed prior to use.
  • Step 4 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine
  • 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride salt) (166 g, 614.5 mmol) and 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride salt) (30 g, 111.0 mmol) were suspended in DCM (2.5 L), treated with NaOH (725 mL of 1 M, 725.0 mmol) and stirred at room temperature for 1 hour. The mixture was transferred into a separatory funnel and left standing over night.
  • the DCM phase was separated and the aqueous phase with insoluble material was extracted twice more with DCM (2 x 500mL).
  • the combined brown DCM phases were stirred over magnesium sulfate and charcoal for 1 hour, filtered and the yellow solution concentrated to a volume of ⁇ 500 mL.
  • the solution was diluted with heptane (750 mL) and DCM was removed under reduced pressure at 60 °C to give a cream suspension. It was stirred at room temperature for 1 hour, filtered, washed with cold heptane and dried to give 4-chloro-6- (2,6-dimethylphenyl)pyrimidin-2-amine (157 g, 91%) as a cream solid.
  • Step 5 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine 235 g, 985.5 mmol was dissolved in MeTHF (2.3 L) and cooled in an ice bath under stirring and nitrogen.
  • methyl 3-chlorosulfonylbenzoate (347 g, 1.479 mol) was added in one portion (seems slightly endothermic) and to the cold pale-yellow solution a solution of 2-methyl-butan-2-ol (Lithium salt) (875 mL of 3.1 M, 2.712 mol) (in heptane) was added dropwise over 1.25 hour (exothermic, internal temperature from 0 to 10 °C). The ice bath was removed and the greenish solution was stirred for 4 hours at room temperature.
  • 2-methyl-butan-2-ol Lithium salt
  • the phases were separated and the NaOH phase was washed twice with MeTHF (2 x 500 mL) and the combined organic phases were extracted once with 2M NaOH (1 x 250 mL).
  • the combined NaOH phases were combined, stirred in an ice bath and slowly acidified by addition of HCl (416 mL of 36 %w/w, 4.929 mol) while keeping the internal temperature between 10 and 20 °C.
  • HCl 416 mL of 36 %w/w, 4.929 mol
  • the final pH was adjusted to 2-3 by addition of solid citric acid.
  • the formed yellow tacky suspension was stirred at room temperature overnight to give a cream crisp suspension.
  • the solid was collected by filtration , washed with plenty of water and sucked dry for 3 hours.
  • Example B Preparation of 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)-4-methyl-pentoxy]-6- (2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 1 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • (2R)-2-amino-4-methyl-pentan-1-ol (12.419 g, 105.97 mmol) in anhydrous THF (200 mL) at room temperature under nitrogen was added sodium tert- butoxide (15.276 g, 158.95 mmol).
  • reaction mixture was stirred for 10 minutes and 3-[[4- chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (22.14 g, 52.983 mmol) was added.
  • the reaction mixture was placed on a water bath preheated to 60 °C and stirred for 20 minutes. After cooling to room temperature, di-tert-butyl dicarbonate (69.381 g, 317.90 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (150 mL).
  • the obtained white solid was re-purified by silica gel chromatography using 0-40% acetone (0.15% acetic acid buffer) gradient in hexanes (0.15% acetic acid buffer) to afford 3-[[4- [(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (20.73 g, 61%) as a white solid.
  • ESI-MS m/z calc.598.2461, found 599.4 (M+1) + ; Retention time: 5.85 minutes (LC Method S).
  • Step 2 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt).
  • reaction mixture was stirred at room temperature for 30 minutes.
  • a solution of 3-nitrobenzenesulfonyl chloride (11.57 g, 52.2 mmol) in anhydrous tetrahydrofuran (40 mL) was added to the reaction mixture dropwise at 0 °C.
  • the reaction was stirred at the same temperature for 1 hour.
  • the reaction was quenched with a saturated aqueous solution of sodium bicarbonate (100 mL).
  • the reaction solution was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water (100 mL), dried over anhydrous sodium sulfate, and then concentrated under vacuum.
  • Example D Preparation of N-[4-(2,6-dimethylphenyl)-6-methylsulfonyl-pyrimidin-2-yl]-3- nitro-benzenesulfonamide
  • Step 1 N-[4-(2,6-Dimethylphenyl)-6-methylsulfonyl-pyrimidin-2-yl]-3-nitro- benzenesulfonamide
  • Stage 1 To a 250 mL round-bottomed flask were added N-[4-chloro-6-(2,6- dimethylphenyl)pyrimidin-2-yl]-3-nitro-benzenesulfonamide (14.14 g, 33.76 mmol), sodium thiomethoxide (5.86 g, 83.61 mmol) and NMP (130 mL).
  • Stage 2 To a 250 mL round-bottomed flask containing the product from Stage 1, DCM (120 mL) was added, followed by m-CPBA (77% pure, 27.22 g, 121.5 mmol). This solution was stirred at room temperature for 90 min. The reaction mixture was quenched by transferring to a 1 L-Erlenmeyer flask containing DCM (400 mL) and solid Na2S 2 O 3 (41.15 g, 260.3 mmol). This mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (300 mL), then washed with water (3 ⁇ 400 mL) and saturated aqueous sodium chloride solution (300 mL).
  • Step 2 3-[[4-[(2R)-2-Amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00153] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (20 g, 47.862 mmol) was suspended in a mixture of 2-methyltetrahydrofuran (80 mL) and DMF (20 mL) and the solution was cooled to -5 °C.
  • Step 2 (2R)-5,5,5-Trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanenitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanenitrile [00155] To a DCM (80 mL) solution of 4,4,4-trifluoro-3,3-dimethyl-butanal (113.7 g, 57.540 mmol) (purity about 7.8%) was added MeOH (110 mL). The mixture was cooled with ice-water bath.
  • Step 3 (2R)-5,5,5-Trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanamide and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanamide [00156] To a solution of a 4:1 mixture of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanenitrile and (2S)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanenitrile (14.87 g, 52.300 mmol) in DCM (105 mL) was added sulfuric acid (56.3 g, 551.06 mmol).
  • Step 4 (2R)-5,5,5-Trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentanoic acid [00157] To a solution of (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanamide (11.35 g, 37.541 mmol) in HOAc (50 mL) was added conc. HCl (65 mL of 11.8 M, 767.00 mmol), followed by water (50 mL). A white precipitate appeared. The mixture was heated at 100°C for 66 h. More conc.
  • HCl 40 mL of 11.8 M, 472.00 mmol
  • HOAc 10 mL
  • the mixture was stirred at 100 °C overnight. More HCl in water (20 mL of 6 M, 120.00 mmol) was added. After 7 h at 100°C, more HCl in water (20 mL of 6 M, 120.00 mmol) was added. The mixture was stirred at 100 °C overnight. It became a clear solution. More HCl in water (20 mL of 6 M, 120.00 mmol) was added. The mixture was stirred at 100°C for 7 h, more HCl in water (20 mL of 6 M, 120.00 mmol) was added. The mixture was stirred at 100 °C overnight.
  • Step 5 (2R)-5,5,5-Trifluoro-4,4-dimethyl-2-[[(1R)-1-phenylethyl]amino]pentan-1-ol
  • (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentanoic acid (hydrochloride salt) 13.04 g, 36.267 mmol
  • THF 200 mL
  • LAH in THF 100 mL of 1 M, 100.00 mmol
  • Step 6 (2R)-2-Amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol
  • (2R)-5,5,5-trifluoro-4,4-dimethyl-2-[[(1R)-1- phenylethyl]amino]pentan-1-ol (hydrochloride salt) 11.56 g, 35.482 mmol
  • EtOH 200 mL
  • 10% palladium on carbon 50% wet (5 g, 2.3492 mmol).
  • the mixture was hydrogenated in a Parr shaker hydrogenation apparatus at 40 psi of hydrogen at rt for 9 h.
  • Step 7 3-[[4-[(2R)-2-Amino-5,5,5-trifluoro-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00160] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (6.12 g, 14.65 mmol) and (2R)-2-amino-5,5,5-trifluoro-4,4-dimethyl-pentan-1-ol (hydrochloride salt) (3.27 g, 14.75 mmol) were combined in THF (30 mL) and the resulting suspension was cooled in a water-ice bath.
  • the organic phase was carefully treated with a saturated aqueous solution of sodium carbonate (500ml, strong gas evolution, pH ⁇ 10 at the end).
  • the three-phase mixture was stirred at room temperature for 1 h and the solid was removed by filtration (large glass frit).
  • the phases (yellow cloudy Diethylether phase, colorless water phase) were separated and the organic phase was washed once more with a saturated aqueous solution of sodium carbonate (250 mL), once with 1M sodium thiosulfate (250 mL) and once with brine (250 mL).
  • Step 3 2-[[(1R)-1-Phenylethyl]amino]-3-[1- (trifluoromethyl)cyclopropyl]propanenitrile [00163] 2-[1-(Trifluoromethyl)cyclopropyl]acetaldehyde (102 g, 670.5 mmol) in MeOH (700 mL) was treated with (1R)-1-phenylethanamine (86 mL, 667.1 mmol) and cooled in an ice bath.
  • Step 4 (2R)-2-[[(1R)-1-Phenylethyl]amino]-3-[1- (trifluoromethyl)cyclopropyl]propenamide
  • sulfuric acid (285 mL of 18 M, 5.130 mol) was added it was cooled in an ice bath.
  • the deep orange emulsion was carefully added to a mixture of ice and water (2.2 L) under mechanical stirring to give a yellow three phase mixture which was basified by slow addition of ammonium hydroxide (1.33 L of 30 %w/w, 10.25 mol) under ice cooling (very exothermic, internal temperature kept between 10 and 25°C by adding ice).
  • the yellow emulsion was stirred for 10 minutes at room temperature (pH ⁇ 10), diluted with DCM (500 mL) and the phases were separated.
  • the aqueous phase was washed twice more with DCM (400 and 200 mL) and the combined organic phases were washed once with water/brine 1:1 (500 mL).
  • Step 5 (2R)-2-[[(1R)-1-Phenylethyl]amino]-3-[1- (trifluoromethyl)cyclopropyl]propanoic acid [00165]
  • (2R)-2-[[(1R)-1-phenylethyl]amino]- 3-[1-(trifluoromethyl)cyclopropyl]propanamide (hydrochloride salt) 147 g, 436.5 mmol
  • acetic acid 735 mL
  • HCl 1.3 L of 12 M, 15.60 mol
  • the colorless suspension was carefully heated to 60-65 °C (strong foaming, acetic acid (145 mL) was added) and the suspension was stirred at 60-65 °C for 16 h.
  • the suspension was then slowly heated to 100 °C (over 4 h, strong foaming) and the resulting solution was stirred at 100 °C for another 20 h.
  • the pale-yellow solution was concentrated under reduced pressure at 65 °C to a semisolid mass and it was treated with water (1.5 L).
  • the thick suspension was heated to 70-80 °C and left to cool to room temperature under stirring for 2 h. The solid was collected by filtration, washed with water and sucked dry overnight.
  • Step 6 (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1- (trifluoromethyl)cyclopropyl]propan-1-ol [00166]
  • (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (hydrochloride salt) (135 g, 399.7 mmol) was suspended in THF (2 L) (thick suspension).
  • the grey suspension was cooled in an ice bath and quenched by careful addition of water (44 mL, 2.442 mol), NaOH (41 mL of 6 M, 246.0 mmol) and water (44 mL, 2.442 mol) (high exotherm with first water addition, kept between 5 °C and 30 °C by cooling).
  • the grey suspension was heated to 50-55 ° C for 1 h, by which time a colorless suspension was obtained.
  • the warm suspension was filtered over a pad of Celite covered over magnesium sulfate.
  • Step 7 (2R)-2-Amino-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol [00167]
  • (2R)-2-[[(1R)-1-phenylethyl]amino]-3-[1- (trifluoromethyl)cyclopropyl]propan-1-ol (hydrochloride salt) (63.3 g, 195.5 mmol) was dissolved in EtOH (630 mL) (under warming), and it was treated with Pd/C (6.3 g of 10 %w/w, 5.920 mmol) (12.5g of 50% water wet) and the reaction was stirred under 2 bar of hydrogen at 40 °C for 24 h.
  • Step 8 3-[[4-[(2R)-2-Amino-3-[1-(trifluoromethyl)cyclopropyl]propoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00168] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (19.09 g, 45.68 mmol) and (2R)-2-amino-3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (hydrochloride salt) (10.18 g, 46.35 mmol) were dissolved in THF (100 mL) and cooled in an ice water bath.
  • Example H Preparation of 3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol
  • Step 1 2-[1-(Trifluoromethyl)cyclopropyl]ethyl methanesulfonate
  • a 1000 mL, 3-neck round bottom flask was fitted with a mechanical stirrer, a cooling bath, a J-Kem temperature probe, an addition funnel and a nitrogen inlet/outlet.
  • the vessel was charged under a nitrogen atmosphere with 2-[1-(trifluoromethyl)cyclopropyl]ethanol (125 g, 811.0 mmol) and 2-methyltetrahydrofuran (625 mL) which provided a clear colorless solution.
  • the vessel was charged under a nitrogen atmosphere with 2-[1- (trifluoromethyl)cyclopropyl]ethyl methanesulfonate (50 g, 215.3 mmol) and dimethyl sulfoxide (250 mL) which provided a clear pale yellow solution. Stirring was commenced and the pot temperature was recorded at 19 °C.
  • the vessel was charged with sodium cyanide (13.19 g, 269.1 mmol), added as a solid in one portion. The mixture was heated to a pot temperature of 70 °C and the condition was maintained for 24 h. Upon heating all of the sodium cyanide dissolved and the reaction mixture turned to a light amber suspension.
  • the vessel was subsequently charged under a nitrogen atmosphere with 3-[1- (trifluoromethyl)cyclopropyl]propanenitrile (25 g, 153.2 mmol) and ethyl alcohol (375 mL) which provided a clear amber solution. Stirring was commenced and the pot temperature was recorded at 19 °C. The vessel was then charged with sodium hydroxide (102.1 mL of 6 M, 612.6 mmol), added in one portion. The resulting clear amber solution was heated to a pot temperature of 70 °C and the condition was maintained for 24 h. After cooling to room temperature, the reaction mixture was concentrated to remove the ethyl alcohol.
  • the residual aqueous was diluted with water (150 mL) and then transferred to a separatory funnel and partitioned with methyl tert- butyl ether (50 mL). The aqueous was removed and the pH was adjusted to pH ⁇ 1 with 6 M hydrochloric acid solution. The resulting aqueous solution was transferred to a separatory funnel and partitioned with methyl tert-butyl ether (250 mL). The organic was removed and the residual aqueous was extracted with methyl tert-butyl ether (2 X 150 mL). The combined organic was dried over sodium sulfate (150 g) and then filtered through a glass frit Buchner funnel.
  • Step 4 3-[1-(Trifluoromethyl)cyclopropyl]propan-1-ol [00172]
  • a 1000 mL, 3-neck round bottom flask was fitted with a mechanical stirrer, a cooling bath, an addition funnel, a J-Kem temperature probe and a nitrogen inlet/outlet.
  • the vessel was charged under a nitrogen atmosphere with lithium aluminum hydride pellets (6.775 g, 178.5 mmol).
  • the vessel was then charged under a nitrogen atmosphere with tetrahydrofuran (250 mL). Stirring was commenced and the pot temperature was recorded at 20 °C.
  • the mixture was allowed to stir at room temperature for 0.5 h to allow the pellets to dissolve.
  • the pot temperature of the resulting grey suspension was recorded at 24 °C.
  • the cooling bath was then charged with crushed ice/water and the pot temperature was lowered to 0 °C.
  • the addition funnel was charged with a solution of 3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (25 g, 137.3 mmol) in tetrahydrofuran (75 mL, 3 mL/g) and the clear pale yellow solution was added dropwise over 1 h. After the addition was completed, the pot temperature of the resulting greyish-brown suspension was recorded at 5 °C. The mixture was allowed to slowly warm to room temperature and continue to stir at room temperature for 24 h.
  • the suspension was cooled to 0 °C with a crushed ice/water cooling bath and then quenched by the very slow dropwise addition of water (6.775 mL), followed by 15 wt% sodium hydroxide solution (6.775 mL) and then finally with water (20.32 mL).
  • the pot temperature of the resulting white suspension was recorded at 5 °C.
  • the suspension was continued to stir at ⁇ 5 °C for 30 min and then filtered through a glass frit Buchner funnel with a 20 mm layer of celite. The filter cake was displacement washed with tetrahydrofuran (2 X 150 mL) and then dried under vacuum for 15 min.
  • Example I Preparation of 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]pyridine-2-carboxylic acid
  • Step 1 Methyl 6-benzylsulfanylpyridine-2-carboxylate [00173] To a solution of phenylmethanethiol (28.408 g, 26.800 mL, 228.72 mmol) in THF (600 mL) was added NaH (11.200 g, 60 %w/w, 280.03 mmol) in a few portions at 0°C.
  • Step 2 Methyl 6-chlorosulfonylpyridine-2-carboxylate
  • Step 3 Methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]pyridine-2-carboxylate [00175] A solution of 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (16.63 g, 71.161 mmol) and methyl 6-chlorosulfonylpyridine-2-carboxylate (16.8 g, 71.294 mmol) dissolved in anhydrous THF (680 mL) was cooled to - 78 °C.
  • Lithium bis(trimethylsilyl)amide (143 mL of 1 M, 143.00 mmol) in solution in THF was added dropwise. The mixture was allowed to warm up to 0 °C slowly and then 1M aqueous HCl (146 mL) was added, followed by DI water (680 mL). The THF was evaporated and the aqueous phase was extracted with chloroform (3 x 250 mL). The combined organic layers were washed with saturated aqueous NaCl (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude was recrystallized in 10 % Acetone in hexanes (500 mL).
  • Step 4 6-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]pyridine-2- carboxylic acid [00176] To a solution of methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]pyridine-2-carboxylate (15.79 g, 36.477 mmol) in THF (180 mL) was added aqueous sodium hydroxide (182 mL of 1 M, 182.00 mmol). The reaction was stirred at RT for 1h.
  • Example J Preparation of 3-( ⁇ 4-[(2R)-2- ⁇ [(tert-Butoxy)carbonyl]amino ⁇ -3-methylbutoxy]- 6-(2,6-dimethylphenyl)pyrimidin-2-yl ⁇ sulfamoyl)benzoic acid
  • Step 1 3-( ⁇ 4-[(2R)-2- ⁇ [(tert-Butoxy)carbonyl]amino ⁇ -3-methylbutoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl ⁇ sulfamoyl)benzoic acid
  • a solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (70 mg, 0.1675 mmol) in THF (653.3 ⁇ L) was added to tert-butyl N-[(1R)-1- (hydroxymethyl)-2-methyl-propyl]carbamate (approximately 51
  • Example K Preparation of 3-[[4-[(2R)-2-Amino-3-cyclopropyl-propoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 1 tert-Butyl N-[(1R)-1-(cyclopropylmethyl)-2-hydroxy-ethyl]carbamate
  • Step 2 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)-3-cyclopropyl-propoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00179] A solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (approximately 172.7 mg, 0.4134 mmol), tert-Butyl N-[(1R)-1-(cyclopropylmethyl)-2- hydroxy-ethyl]carbamate (89 mg, 0.4134 mmol), and sodium t-butoxide (approximately 159.0 mg, 1.654 mmol) in THF (2.067 mL) was stirred for 22 hours.
  • Step 3 3-[[4-[(2R)-2-Amino-3-cyclopropyl-propoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00180] A solution of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propoxy]-6- (2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (45 mg, 0.07542 mmol) in HCl (3 mL of 4 M, 12.00 mmol) (in dioxane) was stirred for four hours.
  • Example L Preparation of 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)-2-pyridyl]sulfamoyl]benzoic acid
  • Step 1 4-Chloro-6-(2,6-dimethylphenyl)pyridin-2-amine
  • Toluene (425 mL) and EtOH (213 mL) was added an aqueous solution of Sodium carbonate (115 mL of 2 M, 230.00 mmol) and the reaction mixture was degassed with nitrogen gas for 45 min.
  • Step 2 Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-2-pyridyl]sulfamoyl]benzoate [00182] To a solution of 4-chloro-6-(2,6-dimethylphenyl)pyridin-2-amine (4.9 g, 20.635 mmol) and methyl 3-chlorosulfonylbenzoate (4.9 g, 20.046 mmol) in THF (200 mL) was added dropwise Lithium bis(trimethylsilyl)amide (45 mL of 1 M, 45.000 mmol) at -78 °C under nitrogen.
  • reaction mixture was stirred for 30 minutes at -78 °C; then warmed up to 0 °C and stirred for 2 hours at 0 °C.
  • the reaction was quenched with cold 1.0 M Hydrochloric acid (50 mL) and diluted with water (200 mL).
  • the mixture was extracted with ethyl acetate (2 x 400 mL). The organic layers were combined, washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated.
  • Step 3 3-[[4-chloro-6-(2,6-dimethylphenyl)-2-pyridyl]sulfamoyl]benzoic acid [00183] To a stirring solution of 3-[4-chloro-6-(2,6-dimethyl-phenyl)-pyridin-2-ylsulfamoyl]- benzoic acid methyl ester (5.3 g, 12.3 mmol) in a mixture of tetrahydrofuran (80 mL) and water (80 mL) at room temperature was added lithium hydroxide monohydrate (1.55 g, 36.9 mmol) and the reaction mixture was stirred at 45 C for 2 hours.
  • Step 4 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)-2- pyridyl]sulfamoyl]benzoic acid
  • a 20 mL vial was charged with 3-[[4-chloro-6-(2,6-dimethylphenyl)-2- pyridyl]sulfamoyl]benzoic acid (300 mg, 0.7196 mmol), (2R)-2-amino-4-methyl-pentan-1-ol (110 mg, 0.9387 mmol) and anhydrous tetrahydrofuran (12 mL), in that order.
  • Example M Preparation of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]- (methoxymethyl)sulfamoyl]benzoate
  • Step 1 Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]- (methoxymethyl)sulfamoyl]benzoate
  • Example N Preparation of 3-[[4-[2-amino-4-[1-(trifluoromethyl)cyclopropyl]butoxy]-6- (2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 1 3-[1-(Trifluoromethyl)cyclopropyl]propanal
  • Dess-Martin periodinane (880 mg, 2.075 mmol) was added to a stirred solution of 3- [1-(trifluoromethyl)cyclopropyl]propan-1-ol (350 mg, 1.665 mmol) in anhydrous methylene chloride (10 mL) at 0 °C (ice-water bath) under nitrogen.
  • Step 2 2-(Benzylamino)-4-[1-(trifluoromethyl)cyclopropyl]butanenitrile [00187] To a stirring solution of 3-[1-(trifluoromethyl)cyclopropyl]propanal (854 mg, 5.140 mmol) in acetonitrile (50.09 mL) under nitrogen atmosphere was added benzylamine (561.5 ⁇ L, 5.141 mmol) and trimethylsilylformonitrile (822.4 ⁇ L, 6.168 mmol). bromo(dimethyl)sulfonium bromide (114.1 mg, 0.5141 mmol) was then added and the mixture was stirred 2h.
  • Step 3 2-(Benzylamino)-4-[1-(trifluoromethyl)cyclopropyl]butanoic acid
  • 2-(benzylamino)-4-[1- (trifluoromethyl)cyclopropyl]butanenitrile (1.33 g, 4.711 mmol) in acetic acid (897.3 ⁇ L, 15.78 mmol) in a vial
  • HCl 8.96 mL of 37 %w/v, 90.92 mmol
  • Step 4 2-(Benzylamino)-4-[1-(trifluoromethyl)cyclopropyl]butan-1-ol
  • 2-(benzylamino)-4-[1-(trifluoromethyl)cyclopropyl]butanoic acid 1.32 g, 4.705 mmol
  • THF 28.36 mL
  • LAH 733.3 mg, 18.82 mmol
  • Step 5 3-[[4-[2-(Benzylamino)-4-[1-(trifluoromethyl)cyclopropyl]butoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00190] To a stirring solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (647.3 mg, 1.549 mmol) and 2-(benzylamino)-4-[1- (trifluoromethyl)cyclopropyl]butan-1-ol (500 mg, 1.549 mmol) in THF (9.79 mL) at 0 °C was added KOtBu (770.8 ⁇ L, 6.196 mmol) and the mixture was stirred at 50 °C for 20 min then removed the THF by rotary evaporation, dissolved the residue in DMSO, filtered and chromatographed
  • Example O Preparation of 3-[[4-(2-amino-4,4,4-trifluoro-butoxy)-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 1 3-[[4-[2-(tert-Butoxycarbonylamino)-4,4,4-trifluoro-butoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 2 3-[[4-(2-Amino-4,4,4-trifluoro-butoxy)-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid [00193] A solution of 3-[[4-[2-(tert-butoxycarbonylamino)-4,4,4-trifluoro-butoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (83 mg, 0.1329 mmol) and HCl (4 mL of 4 M, 16.00 mmol) (in dioxane) was stirred for one hour.
  • Example P Preparation of 3-[[4-[(2R)-2-aminopropoxy]-6-(2,6-dimethylphenyl)pyrimidin- 2-yl]sulfamoyl]benzoic acid
  • Step 1 3-[[4-[(2R)-2-(tert-Butoxycarbonylamino)propoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 2 3-[[4-[(2R)-2-Aminopropoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid [00195] A solution of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)propoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (1.65 g, 2.964 mmol) in HCl (8 mL of 4 M, 32.00 mmol) (in dioxane) was stirred for two hours, and the solvent was removed under vacuum.
  • Example Q Preparation of 5-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-2-methyl-pyrazole-3-carboxylic acid
  • Step 1 Ethyl 3-nitro-1H-pyrazole-5-carboxylate [00196] To a solution 3-nitro-1H-pyrazole-5-carboxylic acid (25 g, 159.15 mmol) in EtOH (250 mL) at rt was added acetyl chloride (37.536 g, 34 mL, 478.18 mmol) slowly. The mixture was stirred at reflux for 4 h.
  • Step 2 Ethyl 2-methyl-5-nitro-pyrazole-3-carboxylate [00197] To a solution of ethyl 3-nitro-1H-pyrazole-5-carboxylate (29.6 g, 154.61 mmol) in DMF (200 mL) at 0°C was added potassium carbonate (44.2 g, 319.81 mmol) and iodomethane (34.200 g, 15 mL, 240.95 mmol) dropwise over 15 min. The mixture was stirred at rt overnight. The mixture was cooled with ice-water bath and cold water (600 mL) was added. The precipitate was collected by filtration and washed with cold water.
  • Step 3 Ethyl 5-amino-2-methyl-pyrazole-3-carboxylate [00198] A mixture of ethyl 2-methyl-5-nitro-pyrazole-3-carboxylate (24.74 g, 124.22 mmol), 10% Palladium on carbon 50% wet (8 g, 3.7587 mmol) and MeOH (250 mL) was hydrogenated under hydrogen (balloon) for 24 h. The mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated to give ethyl 5-amino-2-methyl-pyrazole-3- carboxylate (20.88 g, 99%) as white solid.
  • the mixture was cooled to -5°C and a solution of sodium nitrite (9.26 g, 134.21 mmol) in water (50 mL) was added dropwise over 30 minutes, keeping the inner temperature between -6°C and -3°C.
  • the mixture was stirred at -5°C for 30 minutes, cooled to -10°C, and slowly canulated ( ⁇ 25 minutes) to the first solution.
  • the resulting mixture was stirred at 0-5°C (ice-water bath) for 90 minutes. More copper(I) chloride (270 mg, 2.7273 mmol) was added and the resulting mixture was stirred at 0-5°C (ice-water bath) for 1 hour.
  • Step 5 Ethyl 5-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-2- methyl-pyrazole-3-carboxylate
  • 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine 4.8 g, 20.539 mmol
  • THF 140 mL
  • ethyl 5-chlorosulfonyl-2-methyl- pyrazole-3-carboxylate 6.13 g, 23.217 mmol
  • sodium tert-amoxide in toluene (13.9 mL of 40 %w/v, 50.486 mmol
  • the mixture was stirred at rt for 1.5 h.
  • the mixture was slowly poured into a 1 N aqueous HCl (50 mL) at 0 °C.
  • the mixture was diluted with water 100 mL and extracted with EtOAc (3x 100 mL). The combined organic layers were dried over sodium sulfate filtered and concentrated to dryness.
  • Step 6 5-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-2-methyl- pyrazole-3-carboxylic acid [00201] To a solution of ethyl 5-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]- 2-methyl-pyrazole-3-carboxylate (7.62 g, 16.598 mmol) in THF (220 mL) at 0°C was added a solution of NaOH (2.7 g, 67.505 mmol) in water (50 mL) and the mixture was stirred for 20 minutes.
  • Step 7 5-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]-2-methyl-pyrazole-3-carboxylic acid [00202] 5-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-2-methyl-pyrazole-3- carboxylic acid (250 mg, 0.5926 mmol) and (2R)-2-amino-4-methyl-pentan-1-ol (100 ⁇ L) were combined in THF (1.3 mL) and stirred until the reaction mixture became homogeneous.
  • Example R Preparation of 5-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-1-methyl-pyrazole-3-carboxylic acid
  • Step 1 Methyl 5-[(4-methoxyphenyl)methylsulfanyl]-1-methyl-pyrazole-3- carboxylate
  • the mixture was sparged with nitrogen gas for 15 minutes, then added Xantphos (1.24 g, 2.1430 mmol) and Pd2dba3 (980 mg, 1.0702 mmol).
  • the tube was capped and heated in an oil bath set at 100 °C for 5 hours. Once cooled to room temperature, the reaction mixture was transferred to a 1.0-L separatory funnel with water (350 mL) and the aqueous layer was extracted with ethyl acetate (1 x 300 mL, 1 x 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 2 Methyl 5-chlorosulfonyl-1-methyl-pyrazole-3-carboxylate [00204] A solution of methyl 5-[(4-methoxyphenyl)methylsulfanyl]-1-methyl-pyrazole-3- carboxylate (4.74 g, 16.213 mmol) in acetic acid (50 mL) and water (25 mL) was treated with N- chlorosuccinimide (6.6 g, 49.426 mmol) at room temperature for 1.5 hours. The reaction was then quenched by adding to a 2.0-L separatory funnel containing cold water (1.5 L) and the aqueous layer was extracted with MTBE (3 x 250 mL).
  • Step 4 5-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-1-methyl- pyrazole-3-carboxylic acid
  • Step 5 5-[[4-[(2R)-2-Amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-1-methyl-pyrazole-3-carboxylic acid [00207] 5-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-1-methyl-pyrazole-3- carboxylic acid (1.50 g, 3.556 mmol) and (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride salt) (656 mg, 3.912 mmol) were combined and dissolved/suspended in THF (12 mL).
  • Step 2 (4R)-4-(2-Hydroxy-2-methyl-propyl)oxazolidin-2-one
  • Bromo(methyl)magnesium in diethyl ether 105 mL of 3 M, 315.00 mmol
  • THF 150 mL
  • a warm THF (80 mL) solution of benzyl 2-[(4R)-2-oxooxazolidin-4-yl]acetate (18.1 g, 76.944 mmol) was then added dropwise maintaining the temperature below –10 oC.
  • the mixture was warm up to room temperature and stirred for 18 hours.
  • the mixture was added via canula to a solution of acetic acid (85 mL) in water (440 mL) at 0°C.
  • the resultant mixture was stirred for 1 hour at room temperature.
  • the layers were separated.
  • the aqueous layer was saturated with brine (200 mL) and further extracted with 2-methyltetrahydrofuran (3 x 250 mL) and with ethanol/chloroform (1/2, 3 x 330 mL).
  • the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated.
  • the residue was co-evaporated with heptanes (4 x 100 mL).
  • Step 4 3-[[4-[(2R)-2-Amino-4-hydroxy-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00211] To a solution of (2R)-2-amino-4-methyl-pentane-1,4-diol (567 mg, 4.2571 mmol) and 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (1.5 g, 3.5897 mmol) in tetrahydrofuran (6 mL) was slowly added sodium tert-butoxide in tetrahydrofuran (7.2 mL of 2 M, 14.400 mmol) and the mixture was stirred at room temperature for one hour.
  • the reaction was partitioned between ethyl acetate (30 mL) and 1 N hydrochloric acid (30 mL). The aqueous phase was extracted with ethyl acetate (2 x 20 mL) and 2-methyltetrahydrofuran (4 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was triturated with ethyl acetate (20 mL), the precipitate was filtered and washed with ethyl acetate (2 x 10 mL).
  • N- methylmorpholine (3.0360 g, 3.3 mL, 30.016 mmol) was added followed by a slow addition of isobutyl chloroformate (4.1067 g, 3.9 mL, 30.069 mmol) such that the reaction temperature was kept below -10°C.
  • the mixture was stirred for 30 minutes.
  • the solids were quickly filtered and washed with dimethoxyethane (30 mL).
  • the filtrate was cooled to -40°C and a solution of sodium borohydride (1.45 g, 38.327 mmol) in water (15 mL) was added slowly such that the reaction temperature was maintained between -30°C and -15°C.
  • the mixture was stirred for 15 minutes.
  • Step 2 Benzyl 3-[(4R)-2-oxooxazolidin-4-yl]propanoate [00213] To a solution of benzyl (4R)-4-(tert-butoxycarbonylamino)-5-hydroxy-pentanoate (7.98 g, 24.652 mmol) in dichloroethane (80 mL) was added pyridine (48.900 g, 50 mL, 618.21 mmol). p-toluenesulfonic anhydride (8.65 g, 25.972 mmol) was then added and the mixture was stirred at room temperature for 1 hour and then heated to 90 oC for 2 hours.
  • Step 3 (4R)-4-(3-Hydroxy-3-methyl-butyl)oxazolidin-2-one
  • Methylmagnesium bromide 26 mL of 3 M, 78.000 mmol
  • diethyl ether was added to a mixture of toluene (42 mL) and tetrahydrofuran (42 mL) at –20 °C.
  • the mixture was warmed up to room temperature and stirred for 2 hours.
  • the reaction mixture was cooled to 0 °C, quenched with a 10% aqueous acetic acid solution (50 mL) and the resultant mixture was stirred for 1 hour at room temperature.
  • the layers were separated.
  • the aqueous layer was extracted with methyl- THF (3 x 100 mL) and then with dichloromethane (2 x 100 mL).
  • the organic phases were combined, dried on anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 4 (2R)-2-Amino-5-methyl-hexane-1,5-diol [00215]
  • a mixture of (4R)-4-(3-hydroxy-3-methyl-butyl)oxazolidin-2-one (307 mg, 1.7724 mmol), barium hydroxide octahydrate (1.69 g, 5.3572 mmol), ethanol (12 mL) and water (12 mL) was heated at 95 °C to reflux for 2 hours. Reaction mixture was cooled to room temperature before dry ice was slowly added ( ⁇ 1,8g) and mixture was stirred vigorously for 2 days. The suspension was filtered over a Celite pad and rinsed with ethanol ( ⁇ 15 mL).
  • Step 5 3-[[4-[(2R)-2-Amino-5-hydroxy-5-methyl-hexoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00216] To a solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (371 mg, 0.8878 mmol) and (2R)-2-amino-5-methyl-hexane-1,5-diol (261 mg, 1.7729 mmol) in THF cooled down to 0°C was slowly added sodium tert-butoxide (375 mg, 3.9020 mmol).
  • Step 2 5,5-Dimethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxaborinane
  • (2,3,6-trimethylphenyl) trifluoromethanesulfonate (8.2 g, 30.538 mmol)
  • bis(neopentyl glycolato)diboron (20.75 g, 91.861 mmol)
  • potassium acetate (15 g, 152.84 mmol) in 1,4-dioxane (205 mL) was purged by bubbling nitrogen for 15 minutes.
  • Step 3 tert-Butyl N-[4-chloro-6-(2,3,6-trimethylphenyl)pyrimidin-2-yl]carbamate
  • 5,5-Dimethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxaborinane (1.00 g, 4.308 mmol) was combined with tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate (1.88 g, 5.162 mmol) and dissolved in 1,4-dioxane (17 mL).
  • Step 4 4-Chloro-6-(2,3,6-trimethylphenyl)pyrimidin-2-amine
  • tert-Butyl N-[4-chloro-6-(2,3,6-trimethylphenyl)pyrimidin-2-yl]carbamate (1.57 g, 4.514 mmol) was dissolved in dichloromethane (8 mL).
  • a solution of HCl (5 mL of 4 M, 20.00 mmol) in dioxane was added.
  • the reaction mixture was allowed to stir at room temperature overnight.
  • the obtained slurry was diluted with dichloromethane (75 mL) and washed with aqueous NaOH (1 M, 1 ⁇ 75 mL).
  • Step 5 Methyl 3-[[4-chloro-6-(2,3,6-trimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoate
  • 4-Chloro-6-(2,3,6-trimethylphenyl)pyrimidin-2-amine (1.06 g, 4.279 mmol) was dissolved in tetrahydrofuran (21 mL) and cooled to 0 °C before the addition of sodium hydride (428 mg, 10.70 mmol) (60 wt% dispersion in mineral oil). After stirring for 5 minutes, methyl 3- chlorosulfonylbenzoate (1.51 g, 6.435 mmol) was slowly added dropwise.
  • Step 7 3-[[4-[(2R)-2-Amino-4,4-dimethyl-pentoxy]-6-(2,3,6- trimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00223] 3-[[4-Chloro-6-(2,3,6-trimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (317 mg, 0.7340 mmol) and (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride salt) (135 mg, 0.8051 mmol) were combined and dissolved/suspended in tetrahydrofuran (5.0 mL).
  • Example V Preparation of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2-methyl-1- naphthyl)pyrimidin-2-yl]sulfamoyl]benzoic acid
  • Step 1 tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2-methyl-1- naphthyl)pyrimidin-2-yl]carbamate
  • tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate (4.651 g, 11.493 mmol) and Cesium carbonate (6.064 g, 18.612 mmol) in a mixture of DME (30
  • Step 2 4-Chloro-6-(2-methyl-1-naphthyl)pyrimidin-2-amine [00225] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2-methyl-1- naphthyl)pyrimidin-2-yl]carbamate (3.342 g, 5.6890 mmol) in DCM (20 mL) at 0°C was added HCl in dioxane (20 mL of 4 M, 80.000 mmol). The reaction was allowed to reach RT and it was stirred for 3 hours. The reaction was then quenched with aqueous sodium bicarbonate (150 mL) and DCM (100 mL).
  • Step 3 Methyl 3-[[4-chloro-6-(2-methyl-1-naphthyl)pyrimidin-2- yl]sulfamoyl]benzoate
  • a solution of crude 4-chloro-6-(2-methyl-1-naphthyl)pyrimidin-2-amine (2.15 g, 7.4130 mmol) in anhydrous THF (28 mL) was cooled to 0°C. Then a solution of methyl 3- chlorosulfonylbenzoate (2.278 g, 9.7078 mmol) in anhydrous THF (35 mL) was added.
  • Lithium tert-amoxide in heptane (1.3724 g, 4.7 mL of 40 %w/w, 5.8350 mmol) was then added dropwise. The reaction was brought up to room temperature and stirred for 2 hours. The reaction was then quenched with 1M HCl (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 4 3-[[4-Chloro-6-(2-methyl-1-naphthyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00227] To a solution of methyl 3-[[4-chloro-6-(2-methyl-1-naphthyl)pyrimidin-2- yl]sulfamoyl]benzoate (2.554 g, 5.4581 mmol) in THF (51 mL) was added aqueous solution of NaOH (11 mL of 2 M, 22.000 mmol). The solution was stirred for 1 hour. The solution was then quenched with 1M HCl (10 mL) and EtOAc (20 mL).
  • Step 5 3-[[4-[(2R)-2-Amino-4,4-dimethyl-pentoxy]-6-(2-methyl-1- naphthyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00228] To a solution of 3-[[4-chloro-6-(2-methyl-1-naphthyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (2.412 g, 5.3140 mmol) and (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride salt) (1.023 g, 6.1010 mmol) in anhydrous THF (85 mL) was added sodium tert- butoxide (2.054 g, 21.373 mmol).
  • the semi-solid was re- dissolved in MTBE (300 mL) and diluted with heptane (750 mL). The solution was concentrated in vacuo until a cloud point occurred. The slurry was stirred at ambient temperature for 0.5 h. The precipitate was collected, washed with cold heptane and dried in vacuo at ambient temperature (this solid was product and was therefore kept aside). The filtrate was further concentrated in vacuo until a cloud point occurred. The solution was allowed to stand for 48 h affording a thick off-white slurry. The slurry was filtered, and the filter cake was washed with ⁇ 50 mL of cold heptane. The filter cake was combined with the solid kept aside earlier and air- dried for 4 h.
  • Step 2 tert-Butyl N-[(1R,2R)-2-(4-tert-butylphenyl)-2-hydroxy-1-methyl- ethyl]carbamate
  • a solution of tert-butyl N-[(1R)-1-methyl-2-oxo-ethyl]carbamate (101.73 g, 587.3 mmol) in MeTHF (500 mL) was added slowly over 1 h to bromo-(4-tert- butylphenyl)magnesium (1300 mL of 1 M, 1.300 mol) (1 M in MeTHF) in a -35 °C cold bath at a rate which maintained an internal temperature between -2 °C and -15 °C.
  • Step 3 (1R,2R)-2-Amino-1-(4-tert-butylphenyl)propan-1-ol (hydrochloride salt)
  • Stage 2 In a 250-mL round-bottomed flask, the crude product from Stage 1 was dissolved in dioxane (25 mL) and cooled to 0 °C. This solution was treated with a dioxane solution of HCl (75 mL of 4.0 M, 300.0 mmol), and the resulting mixture was warmed to room temperature over 4 h. Evaporation of the resulting slurry in vacuo provided an off-white solid, corresponding to the deprotected intermediate ( ⁇ 28 g, >100% yield).
  • Stage 3 In a 250-mL round-bottomed flask, the crude product from Stage 2 was dissolved in EtOH (100 mL) and water (25 mL), to which potassium carbonate (35.0 g, 253.2 mmol) and benzyl bromide (11.0 mL, 92.48 mmol) were added. This slurry was stirred at room temperature for 69 h, after which it was filtered over Celite, using MeOH (50 mL) to rinse the potassium carbonate and Celite. The filtrate was evaporated in vacuo and this slurry was taken up in DCM (100 mL), filtered over Celite and evaporated in vacuo.
  • Step 3 (1S,2R)-2-[Benzyl(methyl)amino]-1-(5-tert-butyl-2-pyridyl)-4-methyl- pentan-1-ol
  • (2R)-2-[benzyl(methyl)amino]-1-(5-tert-butyl-2-pyridyl)-4-methyl- pentan-1-one 333.9 mg, 0.9472 mmol
  • MeOH 2.0 mL
  • sodium borohydride (45.3 mg, 1.197 mmol) was added.
  • This mixture was stirred at room temperature for 10 min, after which it was quenched with 0.5 N HCl solution (5 mL).
  • Step 4 3-[[4-[(1S,2R)-1-(5-tert-Butyl-2-pyridyl)-4-methyl-2-(methylamino)pentoxy]- 6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00237]
  • Stage 1 In a 50-mL round-bottomed flask, (1S,2R)-2-[benzyl(methyl)amino]-1-(5- tert-butyl-2-pyridyl)-4-methyl-pentan-1-ol (297.4 mg, 0.8389 mmol) was dissolved in PhMe (5 mL), to which 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (360 mg, 0.8615 mmol) was added.
  • Stage 2 In a 20-mL microwave vial equipped with a magnetic stir bar, the crude product from Stage 1 (772.5 mg, assume 0.8615 mmol if quantitative yield in Stage 1) was dissolved in EtOH (5.0 mL). This solution was sparged with a balloon of hydrogen gas for 5 min. The cap was briefly removed, and Pd/C (107.7 mg of 10 %w/w, 0.1012 mmol) was added. This reaction mixture was stirred under a balloon of hydrogen at room temperature for 15 h, after which it was filtered through Celite and rinsed with methanol (10 mL).
  • Step 5 (10S,11R)-10-(5-tert-Butyl-2-pyridyl)-6-(2,6-dimethylphenyl)-11-isobutyl-12- methyl-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 1) [00239] Stage 1: In a 20-mL vial, 3-[[4-[(1S,2R)-1-(5-tert-butyl-2-pyridyl)-4-methyl-2- (methylamino)pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (320 mg, 0.4195 mmol) was dissolved in DMF (5.0 mL).
  • Stage 2 In a 100-mL round-bottomed flask, the purified product from Stage 1 (240 mg, 0.296 mmol) was dissolved in NMP (20 mL), and stirred under nitrogen at 160 °C for 63 h. After this time, the reaction mixture was cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (3 ⁇ 60 mL). The combined organic extracts were washed with water (120 mL) and saturated aqueous sodium chloride solution (120 mL), then dried over sodium sulfate, filtered, and evaporated in vacuo.
  • Example 2 Preparation of Compound 2 Step 1: tert-Butyl N-[(1R)-1-(hydroxymethyl)-3-methyl-butyl]-N-methyl-carbamate [00241] A solution of (2R)-2-[tert-butoxycarbonyl(methyl)amino]-4-methyl-pentanoic acid (0.44 g, 1.794 mmol) and borane-tetrahydrofuran (5.4 mL of 1 M in THF, 5.400 mmol) in THF (9 mL) was stirred for 16 h. The reaction was quenched with 1 M citric acid and extracted with ethyl acetate.
  • Step 2 (2R)-4-Methyl-2-(methylamino)pentan-1-ol
  • Step 5 (4S,5R)-5-[Benzyl(methyl)amino]-2,7-dimethyl-octan-4-ol
  • the reaction was quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and evaporated under vacuum. The residue was purified by silica gel column chromatography with 0-5% methanol in dichloromethane to give 0.3 g of a mixture containing product.
  • reaction was stirred at 40 °C for 18 h.
  • the reaction was quenched with 1 M citric acid, diluted with water, and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated under vacuum.
  • Step 7 3-[[4-(2,6-Dimethylphenyl)-6-[(1S,2R)-1-isobutyl-4-methyl-2- (methylamino)pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00247] A mixture of 3-[[4-[(1S,2R)-2-[benzyl(methyl)amino]-1-isobutyl-4-methyl-pentoxy]- 6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (41 mg, 0.06223 mmol) and dihydroxypalladium (10% w/w, 10 mg, 0.07121 mmol) in methanol (2 mL) was stirred under a hydrogen atmosphere for four hours.
  • Step 8 (10S,11R)-6-(2,6-Dimethylphenyl)-12-methyl-10,11-bis(2-methylpropyl)-9- oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16- hexaene-2,2,13-trione (Compound 2) [00248] A solution of 3-[[4-(2,6-dimethylphenyl)-6-[(1S,2R)-1-isobutyl-4-methyl-2- (methylamino)pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (32 mg, 0.05627 mmol), HATU (26 mg, 0.06838 mmol), and triethylamine (24 ⁇ L, 0.1722 mmol) in DMF (3 mL) was stirred for 15 h.
  • Example 3 Preparation of Compound 3 Step 1: Spiro[3.3]heptan-2-ylmethanol [00249] To a solution of spiro[3.3]heptane-2-carboxylic acid (9.5 g, 67.770 mmol) in tetrahydrofuran (190 mL) cooled in an ice bath, was added dropwise Lithium aluminum hydride (in THF) (82 mL of 1 M, 82.000 mmol) over 15 minutes, maintaining an internal temperature ⁇ 5°C. After the addition was complete, the reaction was stirred at 0-5°C for 1 hour and at room temperature for 2 hours. The resulting mixture was cooled in an ice bath and water (10 mL) was added dropwise.
  • THF Lithium aluminum hydride
  • Step 2 Spiro[3.3]heptane-2-carbaldehyde [00250] To a solution of spiro[3.3]heptan-2-ylmethanol (7.9 g, 59.471 mmol) in dichloromethane (160 mL) was added sodium bicarbonate (29 g, 345.21 mmol) and Dess-Martin periodinane (31 g, 73.089 mmol). The reaction mixture was stirred at room temperature 3 h. A 5% aqueous solution of sodium bicarbonate (200 mL) was added (strong evolution of gas) followed by a 10% w/w aqueous solution of Na 2 S 2 O 3 (200 mL).
  • Step 3 methyl (Z)-2-(tert-butoxycarbonylamino)-3-spiro[3.3]heptan-2-yl-prop-2- enoate and methyl (E)-2-(tert-butoxycarbonylamino)-3-spiro[3.3]heptan-2-yl-prop- 2-enoate [00251] To a stirred solution of methyl 2-(tert-butoxycarbonylamino)-2- dimethoxyphosphoryl-acetate (1.3 g, 4.3735 mmol) and DBU (712.60 mg, 0.7 mL, 4.6809 mmol) in dichloromethane (10 mL) was added spiro[3.3]heptane-2-carbaldehyde (500 mg, 4.0264 mmol).
  • Step 4 Methyl (2R)-2-(tert-butoxycarbonylamino)-3-spiro[3.3]heptan-2-yl- propanoate [00252] Methyl (Z)-2-(tert-butoxycarbonylamino)-3-spiro[3.3]heptan-2-yl-prop-2-enoate (12.9 g, 42.363 mmol) was dissolved in ethanol (185 mL) and dioxane (60 mL). Nitrogen was passed through for about 10 min using a cannula.
  • Step 5 tert-Butyl N-[(1R)-1-(hydroxymethyl)-2-spiro[3.3]heptan-2-yl- ethyl]carbamate [00253] To a solution of methyl (2R)-2-(tert-butoxycarbonylamino)-3-spiro[3.3]heptan-2-yl- propanoate (12.5 g, 42.032 mmol) in tetrahydrofuran (125 mL) was added LiBH 4 (in THF) (55 mL of 2 M, 110.00 mmol) (no exotherm observed). The reaction mixture was stirred at room temperature for 3 hours.
  • reaction mixture was then poured slowly over a saturated aqueous solution of ammonium chloride (150 mL) at 0°C (strong evolution of gas, but no exotherm).
  • the product was extracted with EtOAc (3 x 150 mL).
  • the combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 7 5-Morpholinopyridine-2-carbaldehyde
  • 5-Fluoropyridine-2-carbaldehyde (5 g, 39.97 mmol) was combined with potassium carbonate (22.1 g, 159.9 mmol) and morpholine (7 mL, 80.27 mmol) in DMF (50 mL), and the reaction mixture was heated to 110 °C until completion. After cooling to room temperature, the reaction was diluted with methanol, filtered, and purified. A small quantity of water was added to the filtrate, which was then concentrated under reduced pressure.
  • Step 8 3-[[4-[(2R)-2-Amino-3-spiro[3.3]heptan-2-yl-propoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00256] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (1 g, 2.393 mmol) and (2R)-2-amino-3-spiro[3.3]heptan-2-yl-propan-1-ol (hydrochloride salt) (590 mg, 2.868 mmol) were combined in THF (5 mL) and stirred at room temperature for 5 minutes in a screwcap vial.
  • Step 9 (11R)-6-(2,6-Dimethylphenyl)-12-[(5-morpholino-2-pyridyl)methyl]-2,2- dioxo-11-(spiro[3.3]heptan-2-ylmethyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 3) [00257] 3-[[4-[(2R)-2-Amino-3-spiro[3.3]heptan-2-yl-propoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (50 mg, 0.08090 mmol) was combined with 5-morpholinopyridine-2-carbaldehyde (approximately 18.66 mg, 0.09708 mmol
  • N-Methylmorpholine (approximately 49.10 mg, 53.37 ⁇ L, 0.4854 mmol) was added, followed by CDMT (approximately 18.47 mg, 0.1052 mmol). After 30 minutes the reaction mixture was warmed to room temperature and it was stirred for an additional 2 hours at room temperature. The reaction mixture was then filtered and purified by reverse phase HPLC (1-70% ACN in water, HCl modifier).
  • Step 2 3-[[4-(2,6-Dimethylphenyl)-6-[2-(isobutylamino)ethoxy]pyrimidin-2- yl]sulfamoyl]benzoic acid [00259] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (110 mg, 0.2632 mmol), tert-butyl N-(2-hydroxyethyl)-N-isobutyl-carbamate (117 mg, 0.5384 mmol), and sodium tert-butoxide (132 mg, 1.374 mmol) were dissolved in THF (1 mL) and stirred at room temperature for 16 h.
  • Step 3 6-(2,6-Dimethylphenyl)-12-isobutyl-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 4)
  • Compound 4 [00260] 3-[[4-(2,6-Dimethylphenyl)-6-[2-(isobutylamino)ethoxy]pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (49 mg, 0.09158 mmol), HATU (36 mg, 0.09468 mmol), and triethylamine (50 ⁇ L, 0.3587 mmol) were combined in DMF (1 mL) and stirred for 30 min.
  • reaction mixture was filtered and purified by reverse phase HPLC utilizing a gradient of 1-99% acetonitrile in 5 mM aqueous HCl to yield 6-(2,6-dimethylphenyl)-12- isobutyl-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (21.3 mg, 48%) ESI-MS m/z calc.480.18314, found 481.4 (M+1) + ; Retention time: 1.56 minutes (LC method A).
  • Example 5 Preparation of Compound 5 Step 1: 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-N-(3- hydroxypropyl)-N-(2-pyridylmethyl)benzamide [00261] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (60 mg, 0.1436 mmol) was dissolved in dichloromethane and added to N,N'-diisopropylcarbodiimide. The mixture was allowed to stir at room temperature for 30 minutes.
  • Step 2 6-(2,6-Dimethylphenyl)-2,2-dioxo-13-(2-pyridylmethyl)-9-oxa-2 ⁇ 6 -thia- 3,5,13,20-tetrazatricyclo[13.3.1.14,8]icosa-1(19),4(20),5,7,15,17-hexaen-14-one (Compound 5)
  • Compound 5 [00262] A solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]-N-(3- hydroxypropyl)-N-(2-pyridylmethyl)benzamide (16.1 mg, 0.02844 mmol) in 1-methyl- pyrrolidin-2-one (5 mL) was added to sodium hydride (approximately 11.37 mg, 12.63 ⁇ L, 0.2844 mmol) (60 wt% dispersion in mineral oil).
  • Example 7 Preparation of Compound 6 Step 1: 5-Fluoropyrimidine-2-carbaldehyde [00263] Into a solution of 5-fluoropyrimidine-2-carbonitrile (10 g, 77.993 mmol) in anhydrous THF (200 mL) was added 1.0 M DIBAL-H in toluene (117 mL of 1 M, 117.00 mmol) at -78 °C dropwise for 30 minutes. After the addition, the reaction was stirred for another 2 hours at the same temperature. Methanol (40 mL) was added to the reaction mixture at -78 °C.
  • Step 2 5-Morpholinopyrimidine-2-carbaldehyde
  • morpholine (1.1988 g, 1.2 mL, 13.760 mmol
  • potassium carbonate (3.65 g, 26.410 mmol)
  • the reaction was stirred at 110 °C for 4 hours. After centrifuge, the DMF solution was directly subjected to HPLC purification using 0 to 40% ACN in water (buffered with 0.1% HCl).
  • Step 3 2-Bromo-1-isopropyl-3-methyl-benzene [00265] Into a solution of 2-isopropyl-6-methyl-aniline (23.750 g, 25 mL, 159.15 mmol) in concentrated HBr (240 mL) and water (240 mL) was added a solution of sodium nitrite (13.18 g, 191.03 mmol) in water (100 mL) at 0 °C. After the addition, the reaction was stirred at 0 °C for 20 minutes.
  • Step 4 (2-Isopropyl-6-methyl-phenyl)boronic acid [00266] To a solution of 2-bromo-1-isopropyl-3-methyl-benzene (14.77 g, 69.306 mmol) in anhydrous THF (400 mL) at -78°C was added dropwise n-BuLi in hexanes (33 mL of 2.5 M, 82.500 mmol). The solution was stirred at this temperature for 15 min before adding trimethyl borate (21.436 g, 23 mL, 206.29 mmol) dropwise at the same temperature. After the addition the solution was allowed to warm up to 0°C and stir for 1 hour.
  • Step 5 tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2-isopropyl-6-methyl- phenyl)pyrimidin-2-yl]carbamate [00267] To a mixture of tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2- yl)carbamate (7.57 g, 20.784 mmol), (2-isopropyl-6-methyl-phenyl)boronic acid (3.17 g, 17.805 mmol), cesium carbonate (14.7 g, 45.117 mmol), and Pd(dppf)Cl 2 (1.47 g, 1.8001 mmol) was added a solvent mixture of DME (70 mL) and water (70 mL) that had been degassed for 30 minutes.
  • DME 70 mL
  • water 70 mL
  • reaction vial was being flushed with nitrogen. Once the addition was finished the vial was sealed and heated to 80°C and the reaction mixture was stirred for 2 h. The mixture was then quenched with DI water (40 mL) and EtOAc (70 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 6 4-Dhloro-6-(2-isopropyl-6-methyl-phenyl)pyrimidin-2-amine [00268] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2-isopropyl-6- methyl-phenyl)pyrimidin-2-yl]carbamate (6.02 g, 10.425 mmol) in anhydrous DCM (35 mL) at 0°C was added HCl in dioxane (35 mL of 4 M, 140.00 mmol). The solution was then raised to RT and stirred for 2 hours.
  • Step 7 Methyl 3-[[4-chloro-6-(2-isopropyl-6-methyl-phenyl)pyrimidin-2- yl]sulfamoyl]benzoate [00269] To a solution of 4-chloro-6-(2-isopropyl-6-methyl-phenyl)pyrimidin-2-amine (3.99 g, 12.195 mmol) and methyl 3-chlorosulfonylbenzoate (4.27 g, 18.197 mmol) in anhydrous THF (40 mL) at 0°C was added dropwise lithium tert-amoxide (in heptanes) (8.7600 g, 30 mL of 40 %w/w, 37.244 mmol) and then stirred at this temperature for 5 minutes after addition.
  • lithium tert-amoxide in heptanes
  • Step 8 3-[[4-Chloro-6-(2-isopropyl-6-methyl-phenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid [00270] To a solution of methyl 3-[[4-chloro-6-(2-isopropyl-6-methyl-phenyl)pyrimidin-2- yl]sulfamoyl]benzoate (4.39 g, 7.6357 mmol) in THF (25 mL) was added NaOH (40 mL of 1 M, 40.000 mmol). The reaction was stirred at RT for 4 hours. The reaction was then quenched with 1M HCl (50 mL) and partitioned with EtOAc (30 mL).
  • Step 9 3-[[4-[(2R)-2-Amino-4,4-dimethyl-pentoxy]-6-(2-isopropyl-6-methyl- phenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00271] To a solution of 3-[[4-chloro-6-(2-isopropyl-6-methyl-phenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (1.38 g, 2.9586 mmol) and (2R)-2-amino-4,4-dimethyl-pentan-1-ol (hydrochloride salt) (462 mg, 2.7553 mmol) in anhydrous THF (25 mL) was added sodium tert- butoxide (1.48 g, 15.400 mmol).
  • Step 10 (11R)-11-(2,2-Dimethylpropyl)-6-[2-methyl-6-(propan-2-yl)phenyl]-12- ⁇ [5- (morpholin-4-yl)pyrimidin-2-yl]methyl ⁇ -9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13- trione (Compound 6) [00272] A 4 mL vial was charged with 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2- isopropyl-6-methyl-phenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (53 mg, 0.09183 mmol) , 5-morpholinopyrimidine-2-carbaldehyde (hydrochlor
  • Example 8 Preparation of Compound 7 Step 1: 1-Benzyloxy-2-bromo-3-methyl-benzene [00274] 2-Bromo-3-methyl-phenol (20 g, 104.79 mmol) in DMF (100 mL) was added potassium carbonate (29.000 g, 209.83 mmol) and BnBr (27.322 g, 19 mL, 159.75 mmol) . The reaction was allowed to proceed for 2 h at 60 °C. The reaction mixture was filtered. The filtrate was added water (300 mL) and extracted with ethyl acetate (3 x 50 mL). The organic fractions were combined and dried over anhydrous sodium sulfate.
  • Step 2 2-(2-Benzyloxy-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [00275]
  • 1-benzyloxy-2-bromo-3-methyl-benzene 21 g, 71.981 mmol
  • KOAc 13 g, 132.46 mmol
  • Step 3 tert-Butyl N-[4-(2-benzyloxy-6-methyl-phenyl)-6-chloro-pyrimidin-2-yl]-N- tert-butoxycarbonyl-carbamate [00276] To a slurry of tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2- yl)carbamate (5.6 g, 14.606 mmol) ,2-(2-benzyloxy-6-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (5.6 g, 16.409 mmol) and cesium carbonate (11.7 g, 35.910 mmol) in dimethoxyethane (50 mL) and water (10 mL) was added Pd(dppf)Cl 2 (1 g, 1.3667 mmol) and the mixture vigorously stirred under nitrogen at 80 oC (reflux) for 2
  • Step 4 4-(2-Benzyloxy-6-methyl-phenyl)-6-chloro-pyrimidin-2-amine [00277] tert-Butyl N-[4-(2-benzyloxy-6-methyl-phenyl)-6-chloro-pyrimidin-2-yl]-N-tert- butoxycarbonyl-carbamate (6.8 g, 12.281 mmol) in DCM (20 mL) was added HCl in dioxane (15 mL of 4 M, 60.000 mmol) . The reaction mixture was stirred at rt for 12 h.
  • Step 5 Methyl 3-[[4-(2-benzyloxy-6-methyl-phenyl)-6-chloro-pyrimidin-2- yl]sulfamoyl]benzoate
  • 4-(2-Benzyloxy-6-methyl-phenyl)-6-chloro-pyrimidin-2-amine (hydrochloride salt) (8.5 g, 21.118 mmol) was dissolved in THF (100 mL) and cooled in an ice bath under stirring and nitrogen To the cold solution, methyl 3-chlorosulfonylbenzoate (7.5 g, 31.962 mmol) in solution in THF (20 mL) was added.
  • lithium tert-pentoxide in heptane 17 g, 23.288 mL of 40 %w/w, 72.278 mmol was added dropwise and the reaction was stirred at room temperature for 2 h.
  • the reaction was quenched with HCl 1 N (50 mL).
  • the reaction was diluted with water (50 ml).
  • the aqueous phase was extracted with EtOAc (3 x30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 6 3-[[4-(2-Benzyloxy-6-methyl-phenyl)-6-chloro-pyrimidin-2- yl]sulfamoyl]benzoic acid [00279] Methyl 3-[[4-(2-benzyloxy-6-methyl-phenyl)-6-chloro-pyrimidin-2- yl]sulfamoyl]benzoate (3.7 g, 6.8494 mmol) in THF (40 mL) was added aqueous NaOH (20 mL of 3 M, 60.000 mmol) . The reaction mixture was stirred at room temperature for 2 h. After completion, aqueous HCl (1 M) was added to acidify the solution.
  • Step 7 3-[[4-[(2R)-2-Amino-4,4-dimethyl-pentoxy]-6-(2-benzyloxy-6-methyl- phenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00280] To a solution of 3-[[4-(2-benzyloxy-6-methyl-phenyl)-6-chloro-pyrimidin-2- yl]sulfamoyl]benzoic acid (3.35 g, 6.2407 mmol) and [(1R)-1-(hydroxymethyl)-3,3-dimethyl- butyl]ammonium chloride (1.2 g, 7.0135 mmol) in THF (50 mL) maintained at 5°C with an ice- water bath was added NaOtBu (3 g, 31.216 mmol) and the mixture was stirred at room temperature for 3 h.
  • Step 8 3-[[4-(2-Benzyloxy-6-methyl-phenyl)-6-[(2R)-4,4-dimethyl-2-[(5-morpholino- 2-pyridyl)methylamino]pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00281] 3-[[4-[(2R)-2-Amino-4,4-dimethyl-pentoxy]-6-(2-benzyloxy-6-methyl- phenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (3 g, 4.4450 mmol) was combined with 5-morpholinopyridine-2-carbaldehyde (1.2 g, 5.9309 mmol) in DCM (20 mL) and stirred at rt for 15 minutes.
  • the reaction was stirred at rt for 1h.
  • the reaction was quenched with 10% citric acid aqueous solution (1 mL).
  • the aqueous solution was extracted with ethyl acetate (3 x 5mL).
  • the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum.
  • Example 9 Preparation of Compound 8 and Compound 9 Step 1: 1-(4-Bromophenyl)-2-(methylamino)ethanol [00283] To a nitrogen sparged round bottom flask was added a solution of 2-amino-1-(4- bromophenyl)ethanol (1.33 g, 6.155 mmol) in ethyl formate (40 mL, 495.2 mmol). The reaction solution was heated to reflux under an atmosphere of nitrogen. After 12 h, the volatiles were removed in vacuo to afford the formamide as a colorless solid. To this material was added anhydrous THF (25 mL) and LAH (280 mg, 7.377 mmol) was added at 0 °C.
  • Step 2 3-[[4-[1-(4-Bromophenyl)-2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-6- (2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00284] To a nitrogen sparged round bottom flask was added 3-[[4-chloro-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (895 mg, 2.142 mmol) and a solution of 1-(4-bromophenyl)-2-(methylamino)ethanol (740 mg, 3.216 mmol) in anhydrous THF (20 mL).
  • Step 3 10-(4-Bromophenyl)-6-(2,6-dimethylphenyl)-12-methyl-2,2-dioxo-9-oxa-2 ⁇ 6 - thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13- one (Compound 8) [00285] To a nitrogen sparged round bottom flask was added 3-[[4-[1-(4-bromophenyl)-2- [tert-butoxycarbonyl(methyl)amino]ethoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (634 mg, 0.8909 mmol) and a solution of HCl (2.2 mL of 4 M, 8.800 mmol) in dioxane.
  • Step 2 10-(4-tert-butylphenyl)-6-(2,6-dimethylphenyl)-12-methyl-2,2-dioxo-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen- 13-one (Compound 10), and 11-(4-tert-butylphenyl)-6-(2,6-dimethylphenyl)-12- methyl-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 13) [00288] In a 250-mL flask, 3-[[4-[2-[tert-butoxycarbonyl(methyl)amino
  • Step 3 10-(4-tert-Butylphenyl)-6-(2,6-dimethylphenyl)-12-methyl-2,2-dioxo-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen- 13-one, enantiomer 1 (Compound 11), and 10-(4-tert-butylphenyl)-6-(2,6- dimethylphenyl)-12-methyl-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one, enantiomer 2 (Compound 12) [00290] Racemic 10-(4-tert-Butylphenyl)-6-(2,6-d
  • Example 11 Preparation of Compound 14 Step 1: 3-[[4-[2-(tert-Butoxycarbonylamino)-1-(4-tert-butylphenyl)ethoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00291] To a solution of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (1.22 g, 2.920 mmol) and 2-amino-1-(4-tert-butylphenyl)ethanol (0.66 g, 3.415 mmol) in THF (24 mL) at 0 °C was added sodium tert-butoxide (0.85 g, 8.845 mmol) and the reaction was stirred at this temperature for 1 hour.
  • Step 2 10-(4-tert-butylphenyl)-12-(3,3-dimethylbutyl)-6-(2,6-dimethylphenyl)-2,2- dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 14) [00292] To a solution of 3-[[4-[2-(tert-butoxycarbonylamino)-1-(4-tert-butylphenyl)ethoxy]- 6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (316 mg, 0.4683 mmol) in DCM (5 mL) was added HCl (4N in Dioxane) (5 mL of 4 M, 20.00 mmol) and the reaction mixture stirred at room temperature for
  • the sample was purified by reverse phase HPLC (Phenomenex Luna C18 column (75 ⁇ 30 mm, 5 ⁇ m particle size), gradient: 1-99% acetonitrile in water (5 mM HCl) over 15.0 minutes) which afforded the intermediate 3-[[4-[1-(4-tert- butylphenyl)-2-(3,3-dimethylbutylamino)ethoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid. To that intermediate in DMF (60 ⁇ L) was added HATU (33 mg, 0.08679 mmol).
  • Example 12 Preparation of Compound 15, Compound 16, and Compound 17 Step 1: tert-Butyl N-[2-(3-tert-butylphenyl)-2-hydroxy-ethyl]-N-methyl-carbamate [00293] To a EtOH solution of methanamine (3.7 g of 33 %w/w, 39.31 mmol) was added a solution of 2-bromo-1-(3-tert-butylphenyl)ethanone (500 mg, 1.960 mmol) in EtOH (5 mL) at RT slowly with vigorous stirring. The mixture was stirred at RT for 1 h. Next, sodium borohydride (223 mg, 5.894 mmol) was added portion wise and the mixture was stirred overnight.
  • Step 2 3-[[4-[2-[tert-Butoxycarbonyl(methyl)amino]-1-(3-tert-butylphenyl)ethoxy]- 6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00294] tert-Butyl N-[2-(3-tert-butylphenyl)-2-hydroxy-ethyl]-N-methyl-carbamate (240 mg, 0.7807 mmol) was dissolved in dioxane solution of HCl (3.6 mL of 4 M, 14.40 mmol) and stirred at RT for 3h.
  • Step 3 10-(3-tert-butylphenyl)-6-(2,6-dimethylphenyl)-12-methyl-2,2-dioxo-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen- 13-one, racemic mixture (Compound 16), and 10-(3-tert-butylphenyl)-6-(2,6- dimethylphenyl)-12-methyl-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one, enantiomer 1 (Compound 15), and 10-(3-tert-butylphenyl)-6-(2,6-dimethylphenyl)- 12-
  • Step 2 3-[[4-[(1R)-2-[Benzyl(tert-butoxycarbonyl)amino]-1-phenyl-ethoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00298] 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (approximately 34.04 mg, 0.08147 mmol) was dissolved into a solution of tert-butyl N-benzyl- N-[(2R)-2-hydroxy-2-phenylethyl]carbamate (approximately 40.01 mg, 0.1222 mmol) in tetrahydrofuran (2 mL).
  • Step 3 (10R)-12-Benzyl-6-(2,6-dimethylphenyl)-2,2-dioxo-10-phenyl-9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 18) [00299] 3-[[4-[(1R)-2-[benzyl(tert-butoxycarbonyl)amino]-1-phenyl-ethoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid was dissolved in a solution of HCl in dioxane.
  • Example 14 Preparation of Compound 19 and Compound 20 Step 1: 2-Methylhept-6-en-2-ol [00300] 5-Bromo-pent-1-ene (18.870 g, 15 mL, 126.62 mmol) in diethyl ether (32 mL) was dropwise added to magnesium turnings (3.2 g, 131.66 mmol) in diethyl ether (190 mL). The reaction mixture was stirred at 45 °C for 4 h.
  • the precipitated acid was removed by filtration and the solution was concentrated under reduced pressure. Pentane (20 mL) was added to the residue then the precipitated acid was removed by filtration. The solution was concentrated under reduced pressure. Dichloromethane (670 mL) then methanesulfonic acid (3.7025 g, 2.5 mL, 38.525 mmol) were added. The mixture was stirred at room temperature for 1 h. Saturated aqueous sodium bicarbonate (50 mL) was added, the phases were separated, and the product was extracted with DCM (2 x 60 mL).
  • Step 3 6,6-Dimethyltetrahydropyran-2-carbaldehyde
  • Step 4 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(6,6-dimethyltetrahydropyran-2- yl)methylamino]-4,4-dimethyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00303] 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (100 mg, 0.1821 mmol) and 6,6- dimethyltetrahydropyran-2-carbaldehyde (31 mg, 0.2180 mmol) were combined and stirred in dichloromethane (0.5 mL) for 30 minutes.
  • dichloromethane 0.5 mL
  • Step 5 (11R)-12-[(6,6-Dimethyloxan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(18),4,6,8(19),14,16-hexaene-2,2,13-trione, diastereomer 1 (Compound 19), and (11R)-12-[(6,6-Dimethyloxan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(18),4,6,8(19),14,16-hexaene-2,2,13-trione, diastereomer 2 (Compound 20
  • N-Methylmorpholine (43 mg, 0.4251 mmol) was added at 0 °C. The reaction mixture was allowed to stir overnight at room temperature. The product was isolated by reverse-phase HPLC eluting with a 10-99% acetonitrile/water gradient over 15 minutes with 5 mM acid modifier in the aqueous phase to give two isomers: (11R)-12- [(6,6-dimethyloxan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2-dimethylpropyl)-9-oxa-2 ⁇ 6 - thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(18),4,6,8(19),14,16-hexaene-2,2,13- trione (5.6 mg, 21%) diastereomer 1 was obtained as a white solid.
  • Step 2 (4,4-Dimethyltetrahydrofuran-2-yl)methanol [00306] To a solution of 2,2-dimethylpent-4-en-1-ol (5.18 g, 45.365 mmol) in dichloromethane (100 mL) was added 3-chloroperoxybenzoic acid (12 g, 51.459 mmol) in portions over 10 minutes. The mixture was stirred over 90 h at room temperature. The mixture was dried over sodium sulfate, filtered and concentrated. Pentane (50 mL) was added and the precipitate was removed.
  • Step 3 4,4-Dimethyltetrahydrofuran-2-carbaldehyde
  • a buffered solution of bleach was prepared by dissolving sodium bicarbonate (123 mg, 1.4642 mmol) in sodium hypochlorite aqueous solution (1.7 mL of 1.505 M, 2.5585 mmol).
  • That solution was then added dropwise to a second solution, that was prepared in advance by adding sodium bromide (13 mg, 0.1263 mmol) (dissolved in water (0.1 mL)) and TEMPO (1.5 mg, 0.0096 mmol) to (4,4-dimethyltetrahydrofuran-2-yl)methanol (300 mg, 2.1892 mmol) in dichloromethane (4 mL) maintained at -12 °C.
  • the internal temperature was maintained below -10°C.
  • the reaction mixture was maintained between -12 °C and -10 °C for 15 min.
  • GC-FID (GC method 1B): Retention time: 2.32 minutes.
  • Step 4 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(4,4-dimethyltetrahydrofuran-2- yl)methylamino]-4,4-dimethyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00308] 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (103.6 mg, 0.1821 mmol) and 4,4- dimethyltetrahydrofuran-2-carbaldehyde (28 mg, 0.2185 mmol) were combined and stirred in dichloromethane (0.5 mL) for 30 minutes.
  • Step 5 (11R)-12-[(4,4-Dimethyloxolan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound 21) [00309] 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-2-[(4,4-dimethyltetrahydrofuran-2- yl)methylamino]-4,4-dimethyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (53 mg, 0.08015 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine
  • N-methylmorpholine (41 mg, 0.4054 mmol) was added at 0 °C. The reaction mixture was allowed to stir overnight at room temperature. After filtration, the product was isolated by reverse-phase HPLC eluting with a 30-60% acetonitrile/water gradient over 30 minutes with 5 mM acid modifier in the aqueous phase.
  • Ethyl isobutyrate (10 g, 11.561 mL, 86.090 mmol) was added over 15 min while keeping the temperature between -20 °C and -10 °C and the reaction was stirred for 15 min.
  • DMPU (11.066 g, 10.4 mL, 86.337 mmol) was added over 15 min while keeping the temperature between -20 °C and -10 °C and the reaction was stirred for 15 min.4-Bromobut-1- ene (12.768 g, 9.6 mL, 94.576 mmol) was added over 15 min while keeping the temperature between -20 °C and -10 °C and the reaction was stirred for 15 min.
  • Step 2 2,2-Dimethylhex-5-en-1-ol [00311] To a suspension of lithium aluminum hydride (4 g, 105.39 mmol) in THF (120 mL) cooled at 0 °C was added a solution of ethyl 2,2-dimethylhex-5-enoate (14.6 g, 85.757 mmol) in THF (70 mL) over 20 min. The reaction mixture was stirred at 0 °C for 1 h then at room temperature. After 2 h the reaction mixture was cooled down to 0 °C, diluted with ether (100 mL), and water (4 mL) was added dropwise.
  • Step 3 (5,5-Dimethyltetrahydropyran-2-yl)methanol [00312] To a solution of 2,2-dimethylhex-5-en-1-ol (11.6 g, 53.380 mmol) in dichloromethane (120 mL) at 0°C was added 3-chloroperoxybenzoic acid (13.7 g, 58.749 mmol) and sodium sulfate (3 g). The reaction was stirred 16 h at room temperature. More 3-chloroperoxybenzoic acid (2 g, 8.5764 mmol) was added and the reaction was stirred at room temperature for 20 h. The reaction was filtered, and the cake was washed with pentane (40 mL).
  • Step 5 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(5,5-dimethyltetrahydropyran-2- yl)methylamino]-4,4-dimethyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00314] To a solution of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (200 mg, 0.3642 mmol) in dichloromethane (2.5 mL) was added a solution of 5,5-dimethyltetrahydropyran-2- carbaldehyde (90 mg, 0.4386 mmol) in dichloromethane (2.5 mL) and the reaction was stirred at room temperature for 0.5 h.
  • Sodium triacetoxyborohydride (386 mg, 1.8213 mmol) was added and the reaction was stirred at room temperature for 1.5 h.1 N aqueous HCl was added (10 mL) and the phases were separated. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was evaporated with heptanes (2 x 50 mL).
  • Step 6 (11R)-6-(2,6-Dimethylphenyl)-11-(2,2-dimethylpropyl)-12-[(5,5- dimethyltetrahydropyran-2-yl)methyl]-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one [00315] To a 0 °C solution of N-methylmorpholine (165.60 mg, 180 ⁇ L, 1.6372 mmol) in DMF (30 mL) was added 2-chloro-4,6- dimethoxy-1,3,5- triazine (90 mg, 0.5126 mmol) followed by 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-2-[(5,5-dimethyltetrahydropyran-2- yl)methyl
  • Step 7 (11R)-12-[(5,5-Dimethyloxan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, diastereomer 1 (Compound 22), and (11R)-12-[(5,5-dimethyloxan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, diastereo
  • Example 17 Preparation of Compound 24 and Compound 25 Step 1: Ethyl 3,3-dimethylhex-5-enoate [00317] LiCl (3.15 g, 74.303 mmol) was added to a solution of diethyl 2-(1,1-dimethylbut-3- enyl)propanedioate (9.4 g, 38.793 mmol) in DMSO (50 mL) and water (1 mL) and heated at 160°C for 48 h. The reaction was cooled and diluted with brine and diethyl ether. The aqueous layer was extracted with diethyl ether.
  • Step 2 3,3-Dimethylhex-5-en-1-ol [00318] To a suspension of LAH (1.4 g, 36.886 mmol) in dry diethylether (30 mL) was added at 0 °C a solution of ethyl 3,3-dimethylhex-5-enoate (5.7 g, 33.48 mmol) in dry diethyl ether (10 mL). The mixture was stirred for 30min at 0 °C and overnight at room temperature. Then, water (20ml) and a solution of NaOH 1M (20 mL) was added carefully to the mixture and stirred 1 h. The resulting mixture was filtered through a Celite pad.
  • Step 3 (4,4-Dimethyltetrahydropyran-2-yl)methanol [00319] To a solution of 3,3-dimethylhex-5-en-1-ol (2.4 g, 18.719 mmol) in dichloromethane (40 mL) at 0°C was added m-CPBA (5.23 g, 22.427 mmol). The reaction was stirred 16 h at room temperature. The reaction was filtered, and the cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure and the yielded white solid was washed with pentane (100 mL). The filtrate was concentrated under reduced pressure and the resulting oil was diluted in DCM (100 mL).
  • Step 4 4,4-Dimethyltetrahydropyran-2-carbaldehyde
  • a 0 °C solution of (4,4-dimethyltetrahydropyran-2-yl)methanol (1.135 g, 7.8704 mmol) in water-saturated DCM (10 mL) was added Dess-Martin periodinane (3.4 g, 8.0162 mmol) and the reaction was stirred for 30 min at room temperature.
  • a mixture of aqueous saturated solutions of sodium thiosulfate (5 mL), saturated sodium bicarbonate (5 mL), water (2 mL) and 1N NaOH (4 mL, to reach pH 9) was added and the reaction mixture was stirred for 5 min.
  • Step 5 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(4,4-dimethyltetrahydropyran-2- yl)methylamino]-4,4-dimethyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00321] To a solution of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (265 mg, 0.4826 mmol) in dichloromethane (8 mL) was added 4,4-dimethyltetrahydropyran-2-carbaldehyde (127 mg, 0.5805 mmol) and the reaction was stirred at room temperature for 0.5 h and sonicated during 5 min.
  • dichloromethane 8 mL
  • Sodium triacetoxyborohydride (512 mg, 2.3433 mmol) was added and the reaction was stirred at room temperature for 1.5 h. Then, 1 N aqueous HCl was added (10 mL) and the phases were separated. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was evaporated with heptanes (2 x 25 mL) to remove residual acetic acid.
  • Step 6 (11R)-6-(2,6-dimethylphenyl)-11-(2,2-dimethylpropyl)-12-[(4,4- dimethyltetrahydropyran-2-yl)methyl]-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one, diastereomer 1 (Compound 24), and (11R)-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-12-[(4,4-dimethyltetrahydropyran-2-yl)methyl]-2,2-dioxo-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hex
  • reaction mixture was stirred at 0 °C for 1 h then at room temperature for 1h.
  • the reaction mixture was then cooled down to 0 °C, diluted with ether (150 mL), and water (5 mL) was added dropwise.
  • Aqueous NaOH (1 N, 10 mL) was subsequently added followed by water (15 mL).
  • the reaction mixture was then stirred at room temperature and sodium sulfate (20 g) was added. After overnight stirring, the mixture was filtered, rinsing the cake with diethyl ether (3 x 100 mL).
  • Step 2 (3,3-Dimethyltetrahydrofuran-2-yl)methanol [00324] To a solution of 3,3-dimethylpent-4-en-1-ol (9.08 g, 79.520 mmol) in dichloromethane (140 mL) at 0°C was added 3-Chloroperoxybenzoic acid (37 g, 158.66 mmol) and sodium sulfate (20 g). The reaction was allowed to warm to room temperature and stirred overnight, after which time all the starting material was consumed (TLC, heptane/EtOAc 7/3, v/v).
  • Step 3 3,3-Dimethyltetrahydrofuran-2-carbaldehyde
  • oxalyl chloride 552.90 mg, 380 ⁇ L, 4.3561 mmol
  • dry dichloromethane 20.800 mL
  • Dimethylsulfoxide 660.60 mg, 600 ⁇ L, 8.4547 mmol
  • 3,3- dimethyltetrahydrofuran-2-yl)methanol 520 mg, 3.9943 mmol
  • Step 4 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-2-[(3,3-dimethyltetrahydrofuran-2- yl)methylamino]-4,4-dimethyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00326] To a solution of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (210 mg, 0.3825 mmol) in dichloromethane (2.5 mL) was added a solution of 3,3-dimethyltetrahydrofuran-2- carbaldehyde (245 mg, 0.4588 mmol) in dichloromethane (2.5 mL) and the reaction was stirred at room temperature for 0.5 h.
  • Sodium triacetoxyborohydride (420 mg, 1.9222 mmol) was added and the reaction was stirred at room temperature for 1.5 h.1 N aqueous HCl was added (10 mL) and the phases were separated. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was co-evaporated with heptanes (2 x 50 mL).
  • Step 5 (11R)-6-(2,6-Dimethylphenyl)-11-(2,2-dimethylpropyl)-12-[(3,3- dimethyltetrahydrofuran-2-yl)methyl]-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one [00327] To a 0 °C solution of N-methylmorpholine (130 mg, 0.1413 mL, 1.2724 mmol) in DMF (32.
  • Step 6 (11R)-12-[(3,3-dimethyloxolan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, diastereomer 1 (Compound 26), and (11R)-12-[(3,3-dimethyloxolan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, diaste
  • Example 19 Preparation of Compound 28 and Compound 29 Step 1: 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(2,2-dimethyltetrahydropyran-4- yl)methylamino]-4,4-dimethyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00329] 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (100 mg, 0.1730 mmol) and 2,2- dimethyltetrahydropyran-4-carbaldehyde (30 mg, 0.2110 mmol) were combined and suspended in dichloromethane (0.5 mL).
  • Step 2 (11R)-12-[(2,2-Dimethyloxan-4-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(18),4,6,8(19),14,16-hexaene-2,2,13-trione, diastereomer 1 (Compound 28), and (11R)-12-[(2,2-dimethyloxan-4-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(18),4,6,8(19),14,16-hexaene-2,2,13-trione, diastereomer 2 (Compound 29) [
  • Step 2 (11R)-6-(2,6-Dimethylphenyl)-11-(2,2-dimethylpropyl)-12-[(2,2,6,6- tetramethyloxan-4-yl)methyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetraazatricyclo[12.3.1.14,8]nonadeca-1(18),4,6,8(19),14,16-hexaene-2,2,13-trione (Compound 30) [00332] (R)-3-(N-(4-((4,4-dimethyl-2-(((2,2,6,6-tetramethyltetrahydro-2H-pyran-4- yl)methyl)amino)pentyl)oxy)-6-(2,6-dimethylphenyl)pyrimidin-2-yl)sulfamoyl)benzoic acid (46 mg, 0.06898 mmol) and 2-chloro-4,6-dimethoxy-1,3,
  • Example 21 Preparation of Compound 31 and Compound 32 Step 1: (6,6-Dimethyltetrahydropyran-3-yl)methanol [00333] To a suspension of lithium aluminum hydride (910 mg, 22.777 mmol) in THF (25 mL) cooled at 0 °C was added a solution of 6,6-dimethyltetrahydropyran-3-carboxylic acid (3 g, 18.964 mmol) in THF (12 mL) over 10 minutes. The reaction mixture was stirred at 0 °C for 1 hour then at room temperature for 2 hours. The reaction mixture was then cooled down to 0 °C, diluted with ether (50 mL) and water (4 mL) was added dropwise.
  • ether 50 mL
  • Step 3 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(6,6-dimethyltetrahydropyran-3- yl)methylamino]-4,4-dimethyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00335] To a solution of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (200 mg, 0.3642 mmol) in dichloromethane (2.5 mL) was added a solution of 6,6-dimethyltetrahydropyran-3- carbaldehyde (120 mg, 0.5485 mmol) in dichloromethane (2.5 mL) and the reaction was stirred at room temperature for 30 minutes.
  • dichloromethane
  • Step 4 (11R)-6-(2,6-Dimethylphenyl)-11-(2,2-dimethylpropyl)-12-[(6,6- dimethyltetrahydropyran-3-yl)methyl]-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one, diastereomer 1 (Compound 31), and (11R)-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-12-[(6,6-dimethyltetrahydropyran-3-yl)methyl]-2,2-dioxo-9-oxa- 2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hex
  • the resulting organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
  • the crude was purified twice by reverse phase chromatography using a 50 g cartridge, eluting with a gradient of MeCN in water (containing 0.1% of formic acid) (5% for 5 CV then 50 to 100% in 20 CV) and by normal phase chromatography using a 12 g cartridge, eluting with a gradient of EtOAc in DCM (0 to 50%).
  • the mixture was then purified by reverse phase chromatography using a 50 g cartridge, eluting with a gradient of MeCN in water (containing 0.1% of formic acid) (5% for 5 CV then 50 to 95% in 20 CV).
  • Example 22 Preparation of Compound 33 and Compound 34 Step 1: 2-Methylhex-5-en-2-ol [00337] Methyl magnesium bromide (Solution in diethyl ether)) (115 mL of 3 M, 345.00 mmol) was diluted with diethyl ether (100 mL). hex-5-en-2-one (17.976 g, 21 mL, 183.16 mmol) was cautiously added dropwise at rt and the resulting mixture was stirred for 1 h at rt. An aqueous NH 4 Cl (saturated solution, 50 mL) followed by aqueous NaHSO4 (1.0 M, 50 mL).
  • Step 2 (5,5-dDmethyltetrahydrofuran-2-yl)methanol
  • 3-Chloroperoxybenzoic acid 25 g, 107.21 mmol
  • 2- methylhex-5-en-2-ol 10 g, 87.577 mmol
  • dichloromethane (193 mL)
  • the mixture was stirred at room temperature for 18 h.
  • the precipitated acid was removed by filtration and the solution was concentrated under reduced pressure. Pentane (100 mL) was added to the residue then the precipitated acid was removed by filtration.
  • Step 4 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(5,5-dimethyltetrahydrofuran-2- yl)methylamino]-4,4-dimethyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00340] To a solution of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (200 mg, 0.3642 mmol) in dichloromethane (3.5 mL) was added a solution of 5,5-dimethyltetrahydrofuran-2- carbaldehyde (75 mg, 0.4389 mmol) in dichloromethane (3.5 mL) and the reaction was stirred at room temperature for 45 min.
  • Sodium triacetoxyborohydride (387 mg, 1.8260 mmol) was added and the reaction was stirred at room temperature for 1 h.1 N aqueous HCl was added (15 mL) and the phases were separated. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was co-evaporated with heptanes (2 x 50 mL).
  • Step 5 (11R)-6-(2,6-Dimethylphenyl)-11-(2,2-dimethylpropyl)-12-[(5,5- dimethyltetrahydrofuran-2-yl)methyl]-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one [00341] To a 0 °C solution of N-methylmorpholine (184.00 mg, 0.2 mL, 1.8191 mmol) in DMF (31 mL) was added 2-chloro-4,6- dimethoxy-1,3,5- triazine (97 mg, 0.5525 mmol) followed by 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-2-[(5,5-dimethyltetrahydrofuran-2- yl)
  • Step 6 (11R)-12-[(5,5-Dimethyloxolan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, diastereomer 1 (Compound 33), and (11R)-12-[(5,5-dimethyloxolan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, diaste
  • Example 23 Preparation of Compound 35 and Compound 36 Step 1: 3,3-Dimethyltetrahydropyran-2-one [00343] LiHMDS (1M in THF) (112 mL of 1 M, 112.00 mmol) was added to a solution of tetrahydropyran-2-one (5 g, 49.942 mmol) and MeI (29.640 g, 13 mL, 208.82 mmol) in THF (150 mL) at -78 °C. The reaction was then allowed to slowly warm to room temperature. After stirring overnight, the reaction mixture was quenched with saturated aq. NH 4 Cl (100 mL).
  • Step 2 3,3-Dimethyl-2-(p-tolylsulfinylmethyl)tetrahydropyran-2-ol
  • LDA solution in hexane/THF/ethylbenzene (25.3 mL of 2 M, 50.600 mmol) was added dropwise to a solution of 1-methyl-4-methylsulfinyl-benzene (3.91 g, 25.352 mmol) in THF (78 mL) with stirring at -78 °C under inert atmosphere.
  • Step 3 3,3-Dimethyl-2-(p-tolylsulfinylmethyl)tetrahydropyran [00345] To a solution of 3,3-dimethyl-2-(p-tolylsulfinylmethyl)tetrahydropyran-2-ol (5.78 g, 20.468 mmol) in dichloromethane (75 mL) was added boron trifluoride ethyl etherate (8.9700 g, 7.8 mL, 63.201 mmol) followed by triethylsilane (5.0232 g, 6.9 mL, 43.200 mmol).
  • the mixture was stirred at room temperature for 18 hours.
  • the mixture was quenched with a saturated aqueous solution of ammonium chloride (100 mL).
  • the phases were separated, and the aqueous layer was extracted with ethyl acetate (2x100 mL).
  • the organic phase was dried over sodium sulfate, filtered and concentrated to dryness.
  • the crude oil was purified by flash chromatography on silica gel (100 g column) eluting with 0% to 50% to afford a 2:1 diastereomeric mixture of 3,3-dimethyl-2-(p-tolylsulfinylmethyl)tetrahydropyran (4.67 g, 84%) as a yellowish solid.
  • Step 4 3,3-Dimethyltetrahydropyran-2-carbaldehyde [00346] To a solution of 3,3-dimethyl-2-(p-tolylsulfinylmethyl)tetrahydropyran (309 mg, 1.1588 mmol) and 2,6-lutidine (425.50 mg, 0.46 mL, 3.9710 mmol) in acetonitrile (13.5 mL) was added trifluoroacetic anhydride (710.17 mg, 0.47 mL, 3.3813 mmol) at 0°C.
  • Step 5 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(3,3-dimethyltetrahydropyran-2- yl)methylamino]-4,4-dimethyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00347] To a solution of 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (100 mg, 0.1821 mmol) in dichloromethane (1.25 mL) was added a solution of 3,3-dimethyltetrahydropyran-2- carbaldehyde (146 mg, 0.3696 mmol) in dichloromethane (1.25 mL) and the reaction was stirred at room temperature for 30 minutes.
  • Step 6 (11R)-6-(2,6-Dimethylphenyl)-11-(2,2-dimethylpropyl)-12-[(3,3- dimethyltetrahydropyran-2-yl)methyl]-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one [00348] To a stirring solution of N-methylmorpholine (193.20 mg, 0.21 mL, 1.9101 mmol) in DMF (22 mL) at 0 °C was added 2-chloro-4,6- dimethoxy-1,3,5- triazine (117 mg, 0.6664 mmol) followed by 3-[[4-(2,6-dimethylphenyl)-6-[(2R)-2-[(3,3-dimethyltetrahydropyran-2- y
  • Step 7 (11R)-12-[(3,3-Dimethyloxan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, diastereomer 1 (Compound 35), and (11R)-12-[(3,3-dimethyloxan-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2- dimethylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, diastereo
  • Example 24 Preparation of Compound 37 Step 1: 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-4-methyl-2-[2-[1- (trifluoromethyl)cyclopropyl]ethylamino]pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00350] 2-[1-(Trifluoromethyl)cyclopropyl]ethanol (approximately 38.66 mg, 0.2508 mmol) was combined with Dess-Martin periodinane (approximately 97.85 mg, 0.2307 mmol) in DCM (0.4 mL). This reaction mixture was stirred for 30 minutes at room temperature.
  • Step 2 (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12- ⁇ 2-[1- (trifluoromethyl)cyclopropyl]ethyl ⁇ -9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13- trione (Compound 37) [00351] 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-4-methyl-2-[2-[1- (trifluoromethyl)cyclopropyl]ethylamino]pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (16 mg, 0.02521 mmol) was combined with HATU (approximately 11.50 mg, 0.03025 mmol) in anhydrous DMF (1 mL
  • This reaction mixture was stirred for 30 minutes at room temperature.0.2 mL of the reaction mixture was then added by syringe to a second vial containing 3-[[4-[(2R)-2-amino- 4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (50 mg, 0.1003 mmol), and acetic acid (approximately 60.23 mg, 57.04 ⁇ L, 1.003 mmol) in DCE (0.3 mL). Sodium cyanoborohydride (approximately 50.42 mg, 0.8024 mmol) was added and the reaction mixture was stirred at room temperature for an additional 2 hours.
  • Step 2 (11R)-12-[(2R)-2,3-Dihydroxypropyl]-6-(2,6-dimethylphenyl)-11-(2- methylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound 38) [00353] The 3-[[4-[(2R)-2-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methylamino]-4-methyl- pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (19 mg, 0.02927 mmol) was combined with HATU (approximately 14.47 mg, 0.03805 mmol)
  • This reaction mixture was stirred for 30 minutes at room temperature. 0.2 mL of the reaction mixture was then added by syringe to a second vial containing 3-[[4- [(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (50 mg, 0.1003 mmol), and acetic acid (approximately 60.23 mg, 57.04 ⁇ L, 1.003 mmol) in DCE (0.3 mL). Sodium cyanoborohydride (approximately 50.42 mg, 0.8024 mmol) was added and the reaction mixture was stirred at room temperature for an additional 2 hours.
  • Step 2 (11R)-12-[(2S)-2,3-Dihydroxypropyl]-6-(2,6-dimethylphenyl)-11-(2- methylpropyl)-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound 39) [00355] 3-[[4-[(2R)-2-[[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methylamino]-4-methyl- pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (17 mg, 0.02619 mmol) was combined with HATU (approximately 12.95 mg, 0.03405 mmol) in
  • reaction mixture was cooled to 0 °C, diluted with 5 mL diethyl ether, then quenched with 1 mL water, followed by 3 mL 1M NaOH.
  • the resulting suspension was warmed to room temperature, then further diluted with diethyl ether and dried using a large quantity of magnesium sulfate.
  • the suspension was filtered, washing with ethyl acetate and concentrated to give the ⁇ 7-oxaspiro[3.5]nonan-2- yl ⁇ methanol (267 mg, 97%) which was used in a later step without additional purification.
  • Step 2 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-4-methyl-2-(7-oxaspiro[3.5]nonan-2- ylmethylamino)pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00357] ⁇ 7-Oxaspiro[3.5]nonan-2-yl ⁇ methanol (approximately 78.35 mg, 0.5015 mmol) was combined with Dess-Martin periodinane (approximately 212.7 mg, 0.5015 mmol) in DCM (0.4 mL).
  • This reaction mixture was stirred for 30 minutes at room temperature.0.2 mL of the reaction mixture was then added by syringe to a second vial containing 3-[[4-[(2R)-2-amino-4- methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (50 mg, 0.1003 mmol), and acetic acid (approximately 60.23 mg, 57.04 ⁇ L, 1.003 mmol) in DCE (0.3 mL). Sodium cyanoborohydride (approximately 50.42 mg, 0.8024 mmol) was added and the reaction mixture was stirred at room temperature for an additional 2 hours.
  • Step 3 (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-12-(7-oxaspiro[3.5]nonan-2- ylmethyl)-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (Compound 40) [00358] 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-4-methyl-2-(7-oxaspiro[3.5]nonan-2- ylmethylamino)pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (12 mg, 0.01884 mmol) was combined with HATU (approximately 9.312 mg, 0.02449 mmol) in DMF (1 mL) and DIPE
  • Step 2 (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2-dioxo-12-[(4-oxo-6,7-dihydro- 5H-pyrazolo[1,5-a]pyrazin-2-yl)methyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 41) [00360] 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-4-methyl-2-[(4-oxo-6,7-dihydro-5H- pyrazolo[1,5-a]pyrazin-2-yl)methylamino]pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (17 mg, 0.02624 mmol) was combined with
  • Step 2 (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-2,2-dioxo-12-[3- (trifluoromethoxy)propyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 42) [00362] (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-3-(methoxymethyl)-2,2-dioxo-12-[3- (trifluoromethoxy)propyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4(19),5,7,14,16-hexaen-13-one (10.4 mg, 0.01598 mmol)
  • Example 30 Preparation of Compound 43 Step 1: Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]- (methoxymethyl)sulfamoyl]benzoate [00363] To a solution of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoate (68.5 g, 158.60 mmol) in DMF (400 mL) at 0 °C was added potassium carbonate (44 g, 318.37 mmol) and chloro(methoxy)methane (13.992 g, 13.2 mL, 173.78 mmol) .
  • Step 3 3-[[4-[(2R)-2-Amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]-(methoxymethyl)sulfamoyl]benzoic acid [00365]
  • 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]- (methoxymethyl)sulfamoyl]benzoic acid (2.6 g, 5.629 mmol), (2R)-2-amino-4-methyl-pentan-1- ol (725 ⁇ L, 5.673 mmol), and sodium tert-butoxide (1.75 g, 18.21 mmol) were combined in THF (7 mL) and stirred at room temperature for 2 h.
  • Step 4 (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-3-(methoxymethyl)-2,2-dioxo-9- oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16- hexaen-13-one [00366] 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]- (methoxymethyl)sulfamoyl]benzoic acid (hydrochloride salt) (797 mg, 1.376 mmol) was dissolved in DMF (6 mL) and added to a solution of HATU (640.2 mg, 1.684 mmol) and triethylamine (766 ⁇ L, 5.496 mmol) in DMF (7 mL).
  • the reaction was stirred at room temperature for 20 min.
  • the reaction mixture was poured into water (20 mL) and the resulting solid was collected via filtration.
  • the solids were dissolved in ethyl acetate and washed with a 1M HCl solution, then brine.
  • Step 5 Ethyl 2-[(11R)-6-(2,6-dimethylphenyl)-11-isobutyl-3-(methoxymethyl)- 2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca- 1(18),4,6,8(19),14,16-hexaen-12-yl]acetate [00367] In a reaction vial, (11R)-6-(2,6-dimethylphenyl)-11-isobutyl-3-(methoxymethyl)-2,2- dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16- hexaen-13-one (135 mg, 0.2573 mmol) was dissolved in DMF (700 ⁇ L) along with sodium
  • the reaction was allowed to stir at 0°C for 5 min then warmed to rt overnight.
  • the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate.
  • the organic layer was isolated, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
  • the crude material was dissolved in DCM (500 ⁇ L) along with TFA (1 mL, 12.98 mmol) and stirred at rt for 1.5 h.
  • Step 2 3-[[4-[[(4S)-3-tert-Butoxycarbonyl-4-phenyl-oxazolidin-2-yl]methoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00371] In a 100-mL round-bottomed flask, 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (2.3023 g, 5.510 mmol) and tert-butyl (4S)-2-(hydroxymethyl)-4- phenyl-oxazolidine-3-carboxylate (1.1509 g, 3.708 mmol) were dissolved in NMP (20 mL), and this solution was cooled to 0 °C.
  • Step 3 3-[[4-(2,6-Dimethylphenyl)-6-(2-oxoethoxy)pyrimidin-2- yl]sulfamoyl]benzoic acid [00372] In a 50-mL round-bottomed flask, 3-[[4-[[(4S)-3-tert-butoxycarbonyl-4-phenyl- oxazolidin-2-yl]methoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (4.9812 g, 2.865 mmol) was dissolved in dioxane (12.0 mL), to which a dioxane solution of HCl (4.0 mL of 4.0 M, 16.00 mmol) was added.
  • dioxane solution of HCl 4.0 mL of 4.0 M, 16.00 mmol
  • the compound was re-purified by preparative TLC (one-sixth of a full silica plate—20 cm x 20 cm, 250 ⁇ m thickness, 60 ⁇ particle size— with 75% ethyl acetate/hexanes, UV active band) to give 12-benzyl-N-tert-butyl-6-(2,6-dimethylphenyl)-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaene-11-carboxamide (1 mg, 4%) .ESI-MS m/z calc.613.2359, found 614.4 (M+1) + ; Retention time: 2.33 minutes; LC method A.
  • Example 32 Preparation of Compound 45 Step 1: tert-Butyl N-[(1R)-1-[[6-(2,6-dimethylphenyl)-2-[[3- [methoxy(methyl)carbamoyl]phenyl]sulfonylamino]pyrimidin-4-yl]oxymethyl]-3- methyl-butyl]carbamate [00374] To a solution of 3-[[4-[(2R)-2-(tert-butoxycarbonylamino)-4-methyl-pentoxy]-6-(2,6- dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (crude 67%, 6.6 g, 7.38 mmol) in DMF (40 mL) were added N,O-dimethylhydroxylamine (hydrochloride salt) (1.62 g, 16.608 mmol), DIPEA (4.3 g, 5.7951 mL, 33.271 mmol) and
  • Step 2 tert-Butyl N-[(1R)-1-[[6-(2,6-dimethylphenyl)-2-[(3- formylphenyl)sulfonylamino]pyrimidin-4-yl]oxymethyl]-3-methyl-butyl]carbamate [00375] To a solution of tert-butyl N-[(1R)-1-[[6-(2,6-dimethylphenyl)-2-[[3- [methoxy(methyl)carbamoyl]phenyl]sulfonylamino]pyrimidin-4-yl]oxymethyl]-3-methyl- butyl]carbamate (282 mg, 0.4394 mmol) in DCM (35 mL) at -78°C was added DIBAL (1.3 mL of
  • Step 3 tert-Butyl N-[(1R)-1-[[6-(2,6-dimethylphenyl)-2-[[3- (hydroxymethyl)phenyl]sulfonylamino]pyrimidin-4-yl]oxymethyl]-3-methyl- butyl]carbamate [00376] To a solution of tert-butyl N-[(1R)-1-[[6-(2,6-dimethylphenyl)-2-[(3- formylphenyl)sulfonylamino]pyrimidin-4-yl]oxymethyl]-3-methyl-butyl]carbamate (4.35 g, 7.4651 mmol) in THF (100 mL) at -70°C was added LAH (5.5 mL of 1 M in THF, 5.5000 mmol) drop
  • the mixture was warmed up to -20°C and stirred at -20°C to -15 °C for 15 min. A gel was formed. Saturated ammonium chloride (100 mL) was added. The mixture was stirred at rt for 40 min and extracted with EtOAc. The organic layer was dried with sodium sulfate.
  • Step 6 (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaene 2,2-dioxide [00379]
  • Step 7 (11R)-6-(2,6-Dimethylphenyl)-11-(2-methylpropyl)-12-[2-(oxan-4-yl)acetyl]- 9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4,6,8(19),14(18),15-hexaene-2,2-dione (Compound 45) [00380] (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaene 2,2-dioxide (40 mg, 0.08573 mmol), 2-tetrahydropyran-4-ylacetic acid (approximately 12.36 mg, 0.08573
  • Example 33 Preparation of Compound 46 Step 1: 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(4-methoxy-4-oxo-butyl)amino]-4- methyl-pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid [00381] 3-[[4-[(2R)-2-amino-4-methyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (293 mg, 0.5147 mmol), methyl 4-oxobutanoate (77.2 mg, 0.6649 mmol), and sodium triacetoxyborohydride (321 mg, 1.515 mmol) were combined in DCM (2 mL) and stirred at room temperature for 2 h.
  • Step 2 4-[(11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-12- yl]butanoic acid [00382] 3-[[4-(2,6-Dimethylphenyl)-6-[(2R)-2-[(4-methoxy-4-oxo-butyl)amino]-4-methyl- pentoxy]pyrimidin-2-yl]sulfamoyl]benzoic acid (106 mg, 0.1770 mmol) was dissolved in DMF (4 mL).
  • HATU (84.7 mg, 0.2228 mmol) was added, followed by triethylamine (100 ⁇ L, 0.7175 mmol) and the reaction was stirred for 30 min at room temperature.
  • the reaction was partitioned between ethyl acetate and a 1M HCl solution. The organics were separated, washed with brine, dried over sodium sulfate and evaporated.
  • the crude material was dissolved in a mixture of THF (2 mL): NaOH (2 mL of 1 M, 2.000 mmol) and the mixture was stirred at room temperature for 2 h.
  • the reaction mixture was partitioned between ethyl acetate and a 1M HCl solution.
  • Step 3 4-[(11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-2,2-dioxo-9-oxa-2 ⁇ 6 -thia- 3,5,12,19-tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-12- yl]butan-1-ol (Compound 46) [00383] 4-[(11R)-6-(2,6-dimethylphenyl)-11-isobutyl-2,2,13-trioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-12-yl]butanoic acid (77 mg, 0.1359 mmol) was dissolved in borane tetrahydrofuran (1 mL of 1 M,
  • Example 34a Preparation of Compound 47 Step 1: (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-[(pyridazin-4- yl)methyl]-9-oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca- 1(17),4,6,8(19),14(18),15-hexaene-2,2-dione (Compound 47) [00384] (11R)-6-(2,6-Dimethylphenyl)-11-isobutyl-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaene 2,2-dioxide (20 mg, 0.04286 mmol), pyridazine-4-carbaldehyde (approximate
  • Example 34b Preparation of Compound 48 Step 1: (11R)-6-(2,6-Dimethylphenyl)-11-(2,2-dimethylpropyl)-12-[(5-morpholino-2- pyridyl)methyl]-2,2-dioxo-9-oxa-2 ⁇ 6 -thia-3,5,12,19- tetrazatricyclo[12.3.1.14,8]nonadeca-1(18),4(19),5,7,14,16-hexaen-13-one (Compound 48) [00385] 3-[[4-[(2R)-2-amino-4,4-dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acid (hydrochloride salt) (250 mg, 0.4553 mmol) was combined with 5- morpholinopyridine-2-carbaldehyde (105 mg, 0.5463 mmol) in DCM (
  • N- methylmorpholine 300 ⁇ L, 2.729 mmol
  • CDMT 100 mg, 0.5696 mmol
  • Step 2 3-[[4-[(2R)-2-[[5-(Cyclopentoxy)-2-pyridyl]methylamino]-4,4-dimethyl- pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid [00388] In a 4 mL vial, to a stirred heterogeneous mixture of 3-[[4-[(2R)-2-amino-4,4- dimethyl-pentoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (hydrochloride salt) (65 mg, 0.1184 mmol) in anhydrous dichloromethane (0.6 mL) were added 5-(cyclopentoxy)pyridine-2-carbaldehyde (23 mg, 0.1203 mmol), and glacial acetic acid (106.733 ⁇ L, 1.877 mmol), in that
  • the vial was purged with nitrogen briefly and capped and stirred for 5 min, then sodium triacetoxyborohydride (130 mg, 0.6134 mmol) was added, followed by addition of DIEA (70 ⁇ L, 0.4019 mmol), and the capped vial was allowed to stir at ambient temperature for 90 min.
  • the reaction mixture (slurry) was stirred at room temperature for 15 min then sodium triacetoxyborohydride (965 mg, 4.553 mmol) was added. After 20 minute and additional sodium triacetoxyborohydride (2.9 g, 13.68 mmol) was added and the reaction was continued to stir for an additional 40 minutes.
  • the reaction mixture was partitioned between ethyl acetate and 1N HCl and saturated aqueous sodium chloride.
  • the reaction mixture was extracted with ethyl acetate (3x) and the organic layer was washed with saturated sodium chloride solution. The organic layer was isolated, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness.
  • the crude material was purified by column chromatography on silica using 10-80% ethyl acetate/hexanes gradient to provide (11R)-12-[(5-bromopyridin-2-yl)methyl]-6-(2,6-dimethylphenyl)-11-(2,2-dimethylpropyl)-9- oxa-2 ⁇ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15- hexaene-2,2,13-trione (910 mg, 30%) as a white solid.

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Abstract

La présente invention concerne des modulateurs du régulateur de la conductance transmembranaire de la fibrose kystique (RTFK) ayant une structure de coeur (I), des compositions pharmaceutiques contenant au moins un tel modulateur, des procédés de traitement de maladies médiées par le RTFK, y compris la fibrose kystique, à l'aide de tels modulateurs et de telles compositions pharmaceutiques, des compositions pharmaceutiques combinées et des polythérapies utilisant ces modulateurs, ainsi que des procédés et des intermédiaires pour fabriquer de tels modulateurs.
PCT/US2021/053858 2020-10-07 2021-10-06 Modulateurs du régulateur de la conductance transmembranaire de la fibrose kystique WO2022076622A2 (fr)

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IL301757A IL301757A (en) 2020-10-07 2021-10-06 Cystic fibrosis transmembrane regulator conductance modulators
CR20230198A CR20230198A (es) 2020-10-07 2021-10-06 Moduladores del regulador de la conductancia transmembrana de la fibrosis quística
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Cited By (8)

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CN116143722A (zh) * 2023-03-09 2023-05-23 南京师范大学 一种次磺酰胺类化合物的合成工艺
WO2023150237A1 (fr) 2022-02-03 2023-08-10 Vertex Pharmaceuticals Incorporated Méthodes de traitement de la fibrose kystique
WO2023150236A1 (fr) 2022-02-03 2023-08-10 Vertex Pharmaceuticals Incorporated Procédés de préparation et formes cristallines de (6a,12a)-17-amino-12-méthyl-6,15-bis(trifluorométhyl)-13,19-dioxa-3,4,18-triazatricyclo[ 12.3.1.12,5]nonadéca-1(18),2,4,14,16-pentaén-6-ol
WO2023196429A1 (fr) * 2022-04-06 2023-10-12 Vertex Pharmaceuticals Incorporated Modulateurs du régulateur de la conductance transmembranaire de la fibrose kystique
WO2023224931A1 (fr) 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Méthodes de traitement de la fibrose kystique
WO2024054845A1 (fr) * 2022-09-07 2024-03-14 Sionna Therapeutics Composés macrocycliques, compositions et leurs procédés d'utilisation
WO2024054840A1 (fr) * 2022-09-07 2024-03-14 Sionna Therapeutics Composés macrocycliques, compositions et procédés d'utilisation associés
WO2024056779A1 (fr) * 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Forme cristalline de (3s,7s,10r,13r)-13-benzyl-20-fluoro-7-isobutyl-n-(2-(3-méthoxy-1,2,4-oxadiazol-5-yl)éthyl)-6,9-diméthyl-1,5,8,11-tétraoxo-10-(2,2,2-trifluoroéthyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tétradecahydro-[1]oxa[4,7,10,14]tétraazacycloheptadécino [16,17-f]quinoléine-3-carboxamide

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